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<?xml version="1.0" encoding="UTF-8"?><feed xmlns="http://www.w3.org/2005/Atom"> <title>Protein Spotlight</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/" /> <link rel="self" type="application/atom+xml" href="https://web.expasy.org/spotlight/atom.xml" /> <id>tag:web.expasy.org,2020-08-20:/spotlight//2</id> <updated>2025-06-23T12:54:05Z</updated> <subtitle>one month, one protein</subtitle> <generator uri="http://www.sixapart.com/movabletype/">Movable Type Pro</generator> <entry> <title>foam etc.</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-281.html" /> <id>tag:web.expasy.org,2025:/spotlight//2.945</id> <published>2025-06-23T12:17:37Z</published> <updated>2025-06-23T12:54:05Z</updated> <summary>The nice thing about shampoo is the foam it produces. When it doesn't, we usually add a little more to froth things up - because foam is a very pleasant part of the procedure. This said, as our thoughts spark off in all directions under the shower, how many of us ever wonder why shampoo foams at all? Foaming agents is the answer. If you're using an eco-friendly shampoo, there's a chance that one of these agents is saponin, an organic chemical found in plants - notably in a plant commonly known as soapwort, soapweed, crow soap or even wild sweet William. Though native to Europe, soapwort grows naturally in many parts of the world, usually in open undisturbed places which many of us would qualify as 'overgrown': on the sides of riverbanks, on roadsides, in fields, in pastures, in rundown gardens and on abandoned home sites. It's the kind of plant we tend to ignore, although scientists are developing a keen interest in it. This is because, besides producing foam, saponins have several biological activities that could be of therapeutic interest. For this reason, a lot of effort has been put into understanding how plants synthesize saponins. It turns out that they are the end product of a metabolic pathway which involves fourteen steps and as many enzymes.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>The nice thing about shampoo is the foam it produces. When it doesn't, we usually add a little more to froth things up - because foam is a very pleasant part of the procedure. This said, as our thoughts spark off in all directions under the shower, how many of us ever wonder why shampoo foams at all? Foaming agents is the answer. If you're using an eco-friendly shampoo, there's a chance that one of these agents is saponin, an organic chemical found in plants - notably in a plant commonly known as soapwort, soapweed, crow soap or even wild sweet William. Though native to Europe, soapwort grows naturally in many parts of the world, usually in open undisturbed places which many of us would qualify as 'overgrown': on the sides of riverbanks, on roadsides, in fields, in pastures, in rundown gardens and on abandoned home sites. It's the kind of plant we tend to ignore, although scientists are developing a keen interest in it. This is because, besides producing foam, saponins have several biological activities that could be of therapeutic interest. For this reason, a lot of effort has been put into understanding how plants synthesize saponins. It turns out that they are the end product of a metabolic pathway which involves fourteen steps and as many enzymes.</p></b> <div class="quoteleft">« The notion of 'metabolic pathway' is not old. Today, it may seem obvious to us that biological compounds are frequently the result of an initial compound that has been tinkered with to produce a final compound - of use to cells or not (waste). But barely 100 years ago, no one was talking about metabolic pathways. It all began with alcohol, or more precisely the wine and brewery industry. Brewers and winemakers wanted to know why - and how - the sweet juice of fruits turns into alcohol. »</div> <p>The notion of 'metabolic pathway' is not old. It may seem obvious to us, now that biological compounds are frequently the result of an initial compound that has been tinkered with to produce a final compound that is either of use to cells or to organisms as a whole (such as ATP, H2O or antibiotics for instance) or is waste (O2 in plants or CO2 in animals for example). But barely 100 years ago, no one was talking about metabolic pathways. It all began with alcohol, or more precisely the wine and brewery industry. Brewers and winemakers wanted to know why - and how - the sweet juice of fruits turns into alcohol. Nowadays the process is called fermentation but it took 300 years of research to understand and unravel the process. <p>Back in 1747, the German chemist Andreas Marggraf announced that glucose was the sweetness to blame. In 1789, the French chemist Antoine Lavoisier revealed that sugars are assemblies of carbon, hydrogen and oxygen. Half a century later, a team of French and German scientists discovered that yeast is responsible for transforming glucose into alcohol - and that yeast is a living cell. The idea that another 'form of life' such as microorganisms could cause fermentation did not go down too well within scientific circles at the time, and it took the work of Louis Pasteur, in 1850, to settle the issue: microorganisms are indeed needed for fermentation. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt281.jpg" alt="laundrette"/><figcaption>Laumdromat 029 by<a href="https://www.donaldyatomi.com/"> Donald Yatomi </a></figcaption><dd><br></dd> <p>oil on canvas<p>courtesy of the artist</figure></div> <div class="quoteright">« Scientists recently managed to determine in detail the metabolic pathway of saponin biosynthesis in one plant: Saponaria officinalis, or soapwort. Although saponins got their name from the Latin sapon meaning soap, they display a wide spectrum of biological actions other than that of being good detergents. Plants produce mixtures of saponins. They are bitter to the taste to ward off large creatures who feed off them, but they also have antifungal, antiparasitic and insecticidal properties against smaller creatures - and these are properties of therapeutic interest. »</div> <p>But how does yeast do it? Today we know that it takes a metabolic pathway known as glycolysis and then fermentation to produce alcohol, and that each step is performed by a different enzyme. The various steps and enzymes involved in glycolysis were only characterized in the 1940s following major advances made by three biochemists Gustav Embden, Otto Meyerhof and Jakub Parnas, and soon followed the conviction that glycolysis was not exclusive to yeast but that it occurs in every single living cell. In fact, glycolysis is just one metabolic pathway among hundreds of others. Possibly thousands. <p>Saponins are the product of a metabolic pathway which only occurs in plants. There are many different types of saponins even within one same plant, in its different tissues and depending on its developmental stage. Quillaja saponaria or the soapbark tree, for instance, synthesizes up to 70 different saponins, all of which have different activities. These different activities are the result of two kinds of building blocks that combine: glycones (oligosaccharides) on the one hand and compounds called aglycones (sapogenol or sapogenein) on the other. In saponins, one aglycone compound forms a scaffold onto which are added one or more glycones. The overall result is an amphiphilic entity where the glycone moieties are water soluble and the aglycone moiety is lipid soluble. This is why saponins make good detergents. Historically, plants that produce saponin like the soapbark tree were boiled down to make soaps for cleaning textiles, especially woollen fabrics. <p>Scientists recently managed to determine in detail the metabolic pathway of saponin biosynthesis in one plant: Saponaria officinalis, or soapwort. Soapwort produces at least 40 different kinds of saponin, but attention was given to the plant's major saponins: saponarioside A (SpA) and saponarioside B (SpB). In a series of elegant assumptions, the team worked out that saponin biosynthesis occurs in a total of 14 steps, each of which is carried out by one distinct enzyme. In a nutshell, in the first four steps of the pathway, the aglycone core scaffold (quillaic acid, QA) is synthesized from one of the most common plant aglycone scaffolds, β-amyrin. Then ten other enzymes move in, one after the other, to prepare and combine glycone (sugar) moieties onto each end of QA. In the very last steps, SpA and SpB are synthesized, where SpA simply has an extra sugar moiety (D-xylose). <p>Metabolic pathways will be metabolic pathways. Today, we know that although you can isolate in theory one pathway, every pathway is linked to another, as they feed each other metabolites. One surprising find in soapwort saponin biosynthesis, however, was the apparent binding of a glycone known as D-quinovose - a sugar moiety more commonly found in marine animals like starfish or sea cucumbers! The origin of D-quinovose in plants remains elusive. However, in soapwort, the research team found that it was added by a noncanonical enzyme, a glycosyl hydrolase (SoGH1) which, unlike the other enzymes, does not localize to the plant cell's vacuole but to its cytosol. It seems, too, that SoGH1 is able to accept a wide range of sugar substrates which guarantees further structural diversity and hence saponin activity. <p>Although saponins got their name from the Latin sapon meaning soap, they display a wide spectrum of biological actions other than that of being good detergents. Plants produce mixtures of saponins - from their roots to their leaves, fruits and seeds - as a means of defence during growth and development. They are bitter to the taste to ward off large creatures who feed off them, but they also have antifungal, antiparasitic and insecticidal properties against smaller creatures - and these are properties of therapeutic interest. To date, saponins have been studied for their anti-inflammatory, immunomodulatory, antibacterial, antiviral, antioxidant, anti-cancer, dermatological, neuroprotective, gastro-intestinal and anti-diabetic properties, not to mention their use in detergents, as flavour modifiers, food preservatives, in cosmetics and as foaming agents in beverages. The list seems endless, and once scientists know exactly how nature builds saponins, you can fine-tune or even lengthen the list by engineering your own. The prospects are promising and varied. In plants, such a variety of one same type of compound is simply another wonderful demonstration of Nature's ability to adapt to different challenging environments over time. </a></em><p><p><div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Jo S., El-Demerdash A., Owen C. et al.<p> Unlocking saponin biosynthesis in soapwort<p> Nature Chemical Biology 21: 215-226(2025)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39043959&query_hl=3&itool=pubmed_docsum">39043959</a></dd><dd>2. Jolly A., Hour Y., Lee Y.-C.<p> An outlook on the versatility of plant saponins: A review<p> Fitoterapia 174: (2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38365071&query_hl=3&itool=pubmed_docsum">38365071</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>beta-amyrin 28-monoxygenase CYP716A379, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1JA93">A0AAW1JA93</a><br></dd><dd>Quillaic acid 3-O-glycosyltransferase CSL1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1HA02">A0AAW1HA02</a><br></dd><dd>Beta-amyrin 28-monooxygenase CYP716A378, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1NEA3">A0AAW1NEA3</a><br></dd><dd>Echinocystic acid 23-monooxygenase, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1J8D7">A0AAW1J8D7</a><br></dd><dd>Glycosyl hydrolase-like protein 1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1I778">A0AAW1I778</a><br></dd><dd>Short-chain dehydrogenase/reductase 1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1NHX6">A0AAW1NHX6</a><br></dd><dd>Beta-amyrin synthase 1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1L0L7">A0AAW1L0L7</a><br></dd><dd>Serine/threonine-protein phosphatase, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1K819">A0AAW1K819</a><br></dd><dd>UDP-glucosyl transferase 73M2, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1J1B8">A0AAW1J1B8</a><br></dd><dd>UDP-glucosyl transferase 73CC6, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1J9R8">A0AAW1J9R8</a><br></dd><dd>UDP-glucosyl transferase 74CD1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1M2U7">A0AAW1M2U7</a><br></dd><dd>UDP-glucosyl transferase 79T1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1IQ05">A0AAW1IQ05</a><br></dd><dd>UDP-glucosyl transferase 79L3, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1MQS1">A0AAW1MQS1</a><br></dd><dd>BAHD acyltransferase 1, <em>Saponaria officinalis</em> (Common soapwort): <a href="http://www.uniprot.org/uniprot/A0AAW1LG41">A0AAW1LG41</a><br></dd> ]]> </content></entry> <entry> <title>a chromosome's glue</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-280.html" /> <id>tag:web.expasy.org,2025:/spotlight//2.944</id> <published>2025-05-20T14:46:24Z</published> <updated>2025-05-20T15:07:16Z</updated> <summary>We all begin with one cell, which divides into two - and so on. It sounds straightforward but a cell has various components (nucleus, mitochondria, Golgi apparatus...) each of which carries out vital activities. If two daughter cells are to survive, they must receive a copy of each component from the mother cell. A mother cell cannot just split in two, pour half of its contents into one cell and tilt the rest in the second. That would be like producing two cars of the same make where one is built with no engine and the other with no wheels. Every part of a cell has a specific and an essential role, which is why each part has to be inherited by progeny. Among these essential components daughter cells must receive a copy of their mother's DNA. The only way to do this is for the mother cell to double its DNA and then distribute it in such a way that the DNA in each daughter cell is identical in quantity and nature. This can occur thanks to a mechanism known as mitosis. During mitosis, a dividing cell's chromosomes (its DNA) alternate between two opposing states: individualized and clustered. It turns out that a protein - already known to scientists - is directly involved in the making of these two chromosomal states. Its name? Ki-67.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>We all begin with one cell, which divides into two - and so on. It sounds straightforward but a cell has various components (nucleus, mitochondria, Golgi apparatus...) each of which carries out vital activities. If two daughter cells are to survive, they must receive a copy of each component from the mother cell. A mother cell cannot just split in two, pour half of its contents into one cell and tilt the rest in the second. That would be like producing two cars of the same make where one is built with no engine and the other with no wheels. Every part of a cell has a specific and an essential role, which is why each part has to be inherited by progeny. Among these essential components daughter cells must receive a copy of their mother's DNA. The only way to do this is for the mother cell to double its DNA and then distribute it in such a way that the DNA in each daughter cell is identical in quantity and nature. This can occur thanks to a mechanism known as mitosis. During mitosis, a dividing cell's chromosomes (its DNA) alternate between two opposing states: individualized and clustered. It turns out that a protein - already known to scientists - is directly involved in the making of these two chromosomal states. Its name? Ki-67.</p></b> <div class="quoteleft">« Before a cell divides, chromosomes are lank and gathered into an indistinctive clump in the nucleus. When a cell is about to divide, however, the chromosomes double their content and tighten up so as to adopt a more rigid shape while breaking away from one another. How do chromosomes switch between their lank formless state and a more rigid condensed one? This puzzled scientists for years until they came up with a very elegant model that involves a protein known as Ki-67. »</div> <p>Mitosis is the process by which cells divide while distributing their contents - in particular their DNA - in a balanced manner to the two daughter cells. Mitosis is billions of years old since the first form of eukaryotic life used it. As a consequence, the process has had plenty of time for refinement, and the intricacies and beauty of its various stages is awe-inspiring. Names have been given to each stage: prophase, metaphase, anaphase and telophase - with an in-between stage called interphase when not much happens. Without going into any detail whatsoever, when a cell is not dividing (interphase), its chromosomes are kept (and protected) within an organelle known as the nucleus. When a cell is dividing (prophase to telophase), its nuclear envelope disassembles thus freeing the chromosomes (that have just been doubled), which are then dispatched to the daughter cells who rapidly reform their own nucleus to protect their own batch of chromosomes. <p>During the various stages of mitosis, chromosomes adopt two major conformations: loose and tight. Before a cell divides, you cannot make out individual chromosomes in the nucleus because they are lank and gathered into an indistinctive clump. When a cell is about to divide, however, the lank chromosomes double their content and tighten up so as to adopt a more rigid shape while breaking away from one another. In this individualized, more rigid conformation, the mother cell can distribute them far more easily, and correctly, to the daughter cells. This is carried out by a structure known as the mitotic spindle - a sort of wonderfully evolved multichord mechanism, which can be compared to the chords of a violin gathered at each end. Each (doubled) chromosome is attached to one chord. As the mother cell halves the chromosomes halve too, and each half is gently pulled into a nascent daughter cell. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt280.jpeg" alt="chromosomes"/><figcaption>Chromosomes Chromatids by<a href="https://www.jennygrayart.com/"> Jenny Gray </a></figcaption><dd><br></dd> <p><p>courtesy of the artist</figure></div> <div class="quoteright">« So phosphorylation and dephosphorylation of Ki-67 would be the key to chromosome individualization and clustering, respectively. However, the role of phosphorylation in this process still has to be demonstrated. For years, Ki-67 has been used both as a marker for cell proliferation and to assess the growth of tumour cells in cancer diagnostics. What is described above remains a model - but it certainly is a very elegant one, and demonstrates how powerful computational models can be. »</div> <p>How do chromosomes switch between their lank formless state and a more rigid condensed one? This puzzled scientists for years until they came up with a very elegant model that involves a protein known as Ki-67. Ki-67 is a large protein, with a high net electrical charge. It seems to have no particular 3D structure and spends most of its time unfolded like spaghetti. However, unlike spaghetti, Ki-67 has an amphiphilic molecular structure: its C-terminus is highly attracted to chromatin (what chromosomes are made of) while its N-terminus prefers the cytoplasm. The body of Ki-67 is made up of repeats that carry over 100 potential phosphorylation sites. Their phosphorylation causes Ki-67 to unfurl into a sort of tail, while dephosphorylation causes the tail to collapse. All in all, the structure of Ki-67 is very similar to that of surfactants, agents that are found at the boundaries of different phases, such as solid and liquid. Does Ki-67 actually behave like a surfactant? At the boundary of chromatin and cytoplasm? <p>This is the model that has been proposed. Ki-67 has no role in the internal structure of chromosomes, that is to say in their condensation as a cell is about to divide for instance. Ki-67's role is simply to keep condensed chromosomes apart during mitosis. It does this by forming a sort of repellent on the chromosomal surface. How? The C-terminus of Ki-67 binds to the chromosome while its extended N-terminus juts out into the cytoplasm. Consider the fact that an estimated 270,000 Ki-67 molecules bind to the surface of a mitotic (condensed) chromosome with an average spacing of about 69nm. Visually, this would look like a very hairy chromosome, whose whole surface is covered with a sort of brush-like arrangement of Ki-67. Since the body of each Ki-67 has a high - and identical - electrical charge, like magnets showing the same poles, two neighbouring chromosomes are repelled. In other words, they'll be kept separated from one another. This is how surfactants behave too. <p>Now, once the individual chromosomes have been dispersed in the daughter cells, they readopt their clumped state in a newly formed nucleus. What happens to the brush-like repellent on their surface? And to Ki-67? It would be natural to assume that since Ki-67 is not needed anymore, it is probably degraded. Scientists suggest something else. In its 'repellent' state, Ki-67 is highly phosphorylated which lends the protein a highly negative charge. At the end of mitosis, the body of Ki-67 is stripped naked as it is dephosphorylated thus giving it a highly positive charge. This might attract negatively-charged stretches of nucleotides known as ribosomal RNA (rRNA) that are found in a cell's nucleus. rRNA acts like a kind of glue as it binds to the 'collapsed tails' of Ki-67, concomitantly bridging neighbouring chromosomes. This is how the temporarily individualized chromosomes stick to one another and cluster in the newly formed nucleus.</p> <p>So phosphorylation and dephosphorylation of Ki-67 would be the key to chromosome individualization and clustering, respectively. However, the role of phosphorylation in this process still has to be demonstrated. Likewise, there is currently no evidence of rRNA actually binding to Ki-67. For years, Ki-67 has been used both as a marker for cell proliferation and to assess the growth of tumour cells in cancer diagnostics. This was until researchers realised that the protein's role was probably less in cell proliferation per se than in the formation of two opposing structural states of chromosomes as a cell divides. Until evidence proves otherwise, what has been described above remains a model - but it certainly is a very elegant one, and demonstrates how powerful computational models can be, and how they are a researcher's precious ally. </a></em><p><p><div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Hernandez-Armendariz A., Sorichetti V., Hayashi Y., et al.<p> A liquid-like coat mediates chromosome clustering during mitotic exit<p> Molecular Cell 84: 3254-3270(2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39153474&query_hl=3&itool=pubmed_docsum">39153474</a></dd><dd>2. Cuylen S., Blaukopf C., Politi A.Z., et al.<p> Ki-67 acts as a biological surfactant to disperse mitotic chromosomes<p> Nature 535: 308-312(2016)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=27362226&query_hl=3&itool=pubmed_docsum">27362226</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Proliferation marker protein Ki-67, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/P46013">P46013</a><br></dd> ]]> </content></entry> <entry> <title>a dark kinase</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-279.html" /> <id>tag:web.expasy.org,2025:/spotlight//2.943</id> <published>2025-04-24T09:33:56Z</published> <updated>2025-04-24T09:55:40Z</updated> <summary>Spermatozoa. There are no other cells in humans - or indeed in any other animals - that have the capacity to wriggle and move forward the way spermatozoa do. Blood cells may dash around our bodies but they can only do so because they are swept up in the pulse and flow of blood. Spermatozoa make progress like little animals - which is why they were called 'animalcules' by the Dutch microbiologist van Leeuwenhoek who was the first to observe them under a microscope in the 17th century. Many organisms can move like spermatozoa, such as bacteria or protists for example, but these are unicellular from the start and really only have themselves to depend upon. Spermatozoa cannot survive on their own, as they don't have the genetic makeup for that, but they can move on their own. In fact, locomotion is really all they have evolved for. Their sole aim is to reach an ovum into which they will inject their DNA. So evolution has trimmed the architecture of spermatozoa down to the very essential: a head (in which resides the nucleus) attached to a powerful tail. The tail itself is a model of biological design and technology brought about by many proteins, among which a crucial kinase known as STK33.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Spermatozoa. There are no other cells in humans - or indeed in any other animals - that have the capacity to wriggle and move forward the way spermatozoa do. Blood cells may dash around our bodies but they can only do so because they are swept up in the pulse and flow of blood. Spermatozoa make progress like little animals - which is why they were called 'animalcules' by the Dutch microbiologist van Leeuwenhoek who was the first to observe them under a microscope in the 17th century. Many organisms can move like spermatozoa, such as bacteria or protists for example, but these are unicellular from the start and really only have themselves to depend upon. Spermatozoa cannot survive on their own, as they don't have the genetic makeup for that, but they can move on their own. In fact, locomotion is really all they have evolved for. Their sole aim is to reach an ovum into which they will inject their DNA. So evolution has trimmed the architecture of spermatozoa down to the very essential: a head (in which resides the nucleus) attached to a powerful tail. The tail itself is a model of biological design and technology brought about by many proteins, among which a crucial kinase known as STK33.</p></b> <div class="quoteleft">« A sperm's journey is an eventful and, usually, a tragic one. Tragic because, although its sole purpose in life is to fertilize an egg, there is little chance this will ever occur. Once a sperm has matured in the male testis and has been sent into a uterus with millions of fellow sperm, by the power of its tail it wiggles and writhes up the uterus making its blind way towards the Fallopian tube with the faint hope of bumping into an egg. »</div> <p>A sperm's journey is an eventful and, more often than not, a tragic one. Tragic because, although its sole purpose in life is to fertilize an egg, there is little chance this will ever occur. Once a sperm has matured in the male testis and has been sent into a uterus with millions of fellow sperm, by the power of its tail it wiggles and writhes up the uterus making its blind way towards the Fallopian tube. There, moving in the opposite direction, one egg will hopefully be maturing as it slowly progresses from the ovary down to the uterus. Hundreds of thousands of sperm run out of stamina or miss the Fallopian tube altogether. Thousands manage to locate the tube, but miss the egg. Hundreds find the egg - but only one manages to worm its way through the egg's protective layers. Once it has, it ensures no other sperm will also succeed by initiating a chemical change in the egg's outer composition to harden it, thus creating a physical barrier. Understandably, such a journey requires endurance and vigour, which is what a sperm's tail is all about. <p>It has taken three hundred years to outline the amazing molecular workings of sperm - ever since the Dutch microbiologist van Leeuwenhoek first described them under his self-made microscope, the lenses of which were initially designed to check the quality of thread used in the fabric he sold in his draper shop. Today we know how sperm mature in the testes, how they move, how they fertilize eggs. We know that they carry their DNA - half of the DNA needed to make a new individual - protected within the walls of a nucleus situated in what has been called the sperm's head. We know that there is a region on the very tip of the head that activates egg fertilization - the acrosome. We know that, without their tail, there would be no fertilization at all, nor journey for that matter, because their tail provides them with locomotion. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt279.jpg" alt="Paul Nash"/><figcaption>The Rye Marshes</figcaption><dd><br></dd> <figcaption>Paul Nash (1889-1946)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Besides being a wonderful example of biological architecture, a sperm's tail is metabolically intricate. It looks like a tail and, on the molecular scale, probably resembles your pet dog's tail in that it has a soft outer layer and a more rigid inner layer that does the wagging. All comparison ends here, however. »</div> <p>Besides being a wonderful example of biological architecture, a sperm's tail is metabolically intricate. It looks like a tail and, on the molecular scale, probably resembles your pet dog's tail in that it has a soft outer layer and a more rigid inner layer that does the wagging. All comparison ends here, however. The outer layer of a sperm's tail consists of a fibrous sheath that also surrounds the sperm's head. A firmer structure known as the axoneme runs from the beginning of the tail to the tip - exactly the same structure you will find in the cilia of protists. It is the axoneme that allows the tail to wriggle. Axonemes are highly-organised structures, consisting largely of proteins known as dynein and tubulin. In a nutshell, tubulin monomers assemble to form pairs of microtubules - 9 outer pairs and one central pair - which each span the length of the sperm's tail. Dynein monomers assemble to form 'dynein arms' that protrude from the outer partner of each microtubule pair. Interaction between the dynein arms and the outer pairs of microtubules create movement - the tail's wag if you like. To enable this, the tail requires energy. This is provided in the form of ATP by mitochondria that are located in the upper part of the tail just below the head - imagine them as the sperm's powerhouse. <p>This is when STK33, serine/threonine kinase 33, makes its appearance. Kinases have pivotal roles in human biology. They are like teachers who clap their hands to pull pupils out of their lethargy. It comes as no surprise, then, that an estimated 538 kinases are to be found in the human genome. How do they perform? Kinases phosphorylate substrates - usually other proteins - by using phosphorus extracted from ATP. Phosphorylation is a common post-translational modification of proteins, the finality of which is to kickstart downstream metabolisms. In the company of almost 200 other kinases, STK33 had been cooped in a corner called 'dark kinases' because very little was known about it. Until a team of researchers discovered that STK33 is involved in a sperm's overall design because when it is absent sperm are unable to move. <p>In particular, they found that without STK33 a sperm's fibrous sheath is misarranged. Now, the fibrous sheath acts as a scaffolding to support structures such as the axoneme, the nucleus and the mitochondrial 'powerhouse'. Without this scaffolding, like a human body that has lost its skeleton, these structures have nothing to hold onto, no template to follow. As a consequence, they are poorly assembled, or not assembled at all, and the sperm loses its means of locomotion. STK33 is like the architect who acts upstream of a project and, predictably, is evolutionarily conserved across the animal kingdom. Do we know which proteins STK33 phosphorylates? Yes. They are called A-kinase anchoring protein 3 and A-kinase anchoring protein 4 (AKAP3 and AKAP4) and are key components of the fibrous sheath. When STK33 is absent, AKAP3/4 are not activated. The fibrous sheath is consequently mal-arranged causing any subsequent structure formation to be mal-assembled - and there is little hope left for a sperm to reach an egg. <p>A greater understanding of kinases such as STK33 could help find therapeutic strategies for men suffering from infertility caused by mutated forms of STK33 for example. Conversely, STK33 could also prove to be a good candidate for male contraception. Today, scientists estimate that about 100 million unintended babies are born every year worldwide. If contraceptive options were not only more successful but also less limited for men, things would change for the better - as they did in the 1960s and 1970s when female contraceptive methods became available in our society. Inhibitors could be designed to block STK33 activity, thus rendering sperm immotile and unable to fertilise an egg. In the absence of inhibitors, STK33 would become functional again and the contraceptive effects reversed. This sounds wonderful. And it is. However, STK33 is not the first contraceptive candidate, many have had to be abandoned because of side effects. Fertility, indeed, cannot be pinned down to one entity. A sperm's environment is influential too - reminding us once again that an organism is never a simple sum of its parts. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Yu W., Li Y., Chen H. et al.<p> STK33 phosphorylates fibrous sheath protein AKAP3/4 to regulate sperm flagella assembly in spermiogenesis<p> Molecular Cell Proteomics 22: (2023)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=37146716&query_hl=3&itool=pubmed_docsum">37146716</a></dd><dd>2. Ku A.F., Sharma K.L., Ta H.M., et al.<p> Reversible male contraception by targeted inhibition of serine/threonine kinase 33<p> Science 384:885-890(2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38781365&query_hl=3&itool=pubmed_docsum">38781365</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Serine/threonine-protein kinase 33, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q9BYT3">Q9BYT3</a><br></dd>]]> </content></entry> <entry> <title>relay</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-278.html" /> <id>tag:web.expasy.org,2025:/spotlight//2.942</id> <published>2025-03-25T09:51:17Z</published> <updated>2025-03-25T10:11:12Z</updated> <summary>Life is a powerful force. From the moment it appeared on Earth - which is estimated at roughly 4.5 billion years ago - it has never ceased to find ways of continuing, plucking from Nature what it needs to create offspring. Rich soil broken down by earthworms feeds the emerging buds of flowers. Grains shed by fruit provide hatchlings with food, and the planet's oceans stock up with plankton to sustain their schools of fish and pods of whales. This team spirit, if you like, is also found on the molecular scale. When mothers lactate, for example, their bodies draw calcium from their own bones to build the bones of their newborn. In the same vein, scientists discovered another relay at work further upstream where maternal factors are activated to replace the calcium that has been removed from the mother's bones. In this way, the mother's bones are not weakened while the baby's bones are strengthened - and life carries on. A maternal brain hormone that is directly involved in rebuilding maternal bone during lactation has recently been discovered. Its name: CCN3. CCN3 is not new to biologists, but its role in fortifying the bones of lactating mothers is. </summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Life is a powerful force. From the moment it appeared on Earth - which is estimated at roughly 4.5 billion years ago - it has never ceased to find ways of continuing, plucking from Nature what it needs to create offspring. Rich soil broken down by earthworms feeds the emerging buds of flowers. Grains shed by fruit provide hatchlings with food, and the planet's oceans stock up with plankton to sustain their schools of fish and pods of whales. This team spirit, if you like, is also found on the molecular scale. When mothers lactate, for example, their bodies draw calcium from their own bones to build the bones of their newborn. In the same vein, scientists discovered another relay at work further upstream where maternal factors are activated to replace the calcium that has been removed from the mother's bones. In this way, the mother's bones are not weakened while the baby's bones are strengthened - and life carries on. A maternal brain hormone that is directly involved in rebuilding maternal bone during lactation has recently been discovered. Its name: CCN3. CCN3 is not new to biologists, but its role in fortifying the bones of lactating mothers is.</p></b> <div class="quoteleft">« When mothers lactate, calcium is extracted from their bones to produce milk and help build the bones of their newborn. It is estimated that bone loss in humans can reach 10%. Under normal circumstances, oestrogen deals with calcium deficiency by promoting bone formation. However, mothers suffer a severe drop in oestrogen levels shortly after delivery. Not so long ago, scientists noticed a surge in CCN3 expression in lactating mothers. »</div> <p>CCN3 belongs to the CCN family of proteins that is composed of six members: CCN1 to CCN6. CCN3 is one of the founding members and was initially called NOV (for Nepthroblastoma Overexpressed). The two other founding members are CCN1 and CCN2, first named CYR61 (for Cystein Rich) and CTGF (for Connective Tissue Growth Factor), respectively. These three proteins were discovered in the early 1990s. When scientists realised that not only were they closely related but they also shared a similar domain structure, they were renamed CCN1-CCN3, where CCN was the acronym of CYR61, CTGF and NOV in that order. Based on their structural features and partial identity, three other proteins soon joined the family - WISP-1, WISP-2 and WISP-3 which were renamed CCN4, 5 & 6 accordingly. This is the field of nomenclature. It is not fun to read, but giving the right names to things can be a real time saver for biologists who are frequently faced with identical proteins, or proteins that belong to one same family, which carry such contrasted names that, unless you are aware, you would never think they were related. Funnily enough and perhaps not surprisingly, like a cat moving silently from one room to another, over the years, the meaning of the acronym CCN has slowly shifted from the first initials of its three founding members to those of Cellular Communication Network. <p>What do CCN proteins have in common? They are probably multimeric complexes and expressed in a wide variety of both adult and embryonic tissues, at highly variable levels. They are cysteine-rich proteins, secreted into the extracellular matrix and, so far, have only been found in vertebrates. It is thought that the six members of the CCN family act together, or sequentially, at given times and locations throughout an organism's life. What do they do? Like switchboard operators, CCN proteins are at the heart of a communication network between cells. Once activated, CCN proteins bind directly to various factors that trigger off multiple signals which, in turn, prompt numerous signalling pathways. Studied in the framework of osteogenesis and angiogenesis, CCN proteins are known to influence cell communication, cell adhesion, cell migration, cell proliferation, cell growth, cell differentiation, cell survival as well as protein production in cells involved in the formation of bone and blood vessels - all things essential for healthy embryonic development, but also for adults. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt278.jpg" alt="Paula Modersohn-Becker"/><figcaption>Nursing mother</figcaption><dd><br></dd> <figcaption>Paula Modersohn-Becker (1876-1907)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« CCN proteins are probably multimeric complexes, expressed in a wide variety of adult and embryonic tissues, at highly variable levels. They are secreted into the extracellular matrix and, so far, have only been found in vertebrates. CCN proteins act together, or sequentially, at given times and locations throughout an organism's life acting like switchboard operators at the heart of a communication network between cells. »</div> <p>How can six members of one family be at the heart of such an astounding variety of biological functions? They owe this to their modular structure and, perhaps also, to the presence of linker regions and a hinge. Indeed, CCN proteins are made up of four modules - 1) an insulin-like growth factor binding protein (IGFBP) motif, 2) a von Willebrand factor (VWC) domain, 3) a thrombospondin type 1 (TSP1) domain and a 4) carboxy-terminal (CT) domain - linked to one another by supple linker domains. Each module can interact independently, or in concert, with several effectors (extracellular matrix proteins, transmembrane proteins, growth factors...). Consequently, CCN proteins engage with a large range of effectors - even larger when considering multimeric complexes of CCN proteins. Together they form a centralized communication network that regulates key signalling pathways leading to cell differentiation, growth, proliferation and so on. It is likely, too, that the four modules communicate with each other in a combinatorial manner to fashion yet other functions - possibly thanks to the presence of those supple linker domains and a hinge between the second and the third modules which could facilitate inter-domain communication. <p>CCN3, as mentioned earlier, is one of the founding members of the CCN family. It is known to be involved in skeletal development and cartilage metabolism where it represses chondrocyte cell proliferation when energy levels are low - thus promoting cell quiescence while environmental conditions are not favourable. As such, CCN3 can be regarded as a metabolic regulator that prevents cells from overworking if conditions are not good. Found in the adrenal gland and in blood, researchers suggest that CCN3 is an adrenal hormone. <p>An intriguing find was made recently. When mothers lactate, calcium is extracted from their bones to produce milk and help build the bones of their newborn. It is estimated that bone loss in rodents - who have large litters - can reach 30% while in humans loss can reach 10%. Under normal circumstances, oestrogen deals with calcium deficiency by promoting bone formation. However, mothers suffer a severe drop in oestrogen levels shortly after delivery - so there must be another mechanism dedicated to lactation to keep calcium levels balanced. This is when scientists noticed a surge in CCN3 expression in lactating mothers. Where? In neurons belonging to a part of the hypothalamus known as the arcuate nucleus which is involved in transmitting appetite signals, themselves reflected by energy stores. So there must be a system that senses low maternal calcium levels. CCN3 is then synthesized and flung, in the manner of a hormone, into the mother's blood to bind to its receptor - probably a growth factor. <p>So in one instance, CCN3 hinders bone formation (cartilage metabolism) while in another (lactation) it promotes bone formation. This seemingly conflicting situation may explain the fact that the roles of CCN proteins are not only defined by a given combination of modules and possible interactions between them but also possibly by proteolytic processing, gene expression regulation - or they may even be susceptible to where they are synthesized - a given tissue or organ - and when - a certain stage of development for instance. Certainly, CCN3 seems to be involved one way or another with bone formation and could prove to be an ideal therapeutic candidate for people suffering from bone diseases among which osteoporosis. Meanwhile, it will continue to relay strength between a mother and her progeny. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Babey M.E., Krause W.C., Chen K. et al.<p> A maternal brain hormone that builds bone<p> Nature 632: (2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38987585&query_hl=3&itool=pubmed_docsum">38987585</a></dd><dd>2. Kubota S., Kawaki H:, Perbal B. et al.<p> Do not overwork: cellular communication network factor 3 for life in cartilage<p> Journal of Cell Communication and Signalling 17:353-359(2023)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=36745317&query_hl=3&itool=pubmed_docsum">36745317</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>CCN family member 3, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/P48745">P48745</a><br></dd><dd>CCN family member 3, <em>Rattus norvegicus</em> (Rat): <a href="http://www.uniprot.org/uniprot/Q9QZQ5">Q9QZQ5</a><br></dd>]]> </content></entry> <entry> <title>the dormant ribosome</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-277.html" /> <id>tag:web.expasy.org,2025:/spotlight//2.941</id> <published>2025-02-28T12:25:22Z</published> <updated>2025-03-02T13:19:08Z</updated> <summary>Snowdrops are here. The tips of daffodil shoots are pushing through the soil, and soft grey buds are preparing to burst on the magnolias. These are reminders that Winter marks the end of one life cycle while Spring marks the one about to begin. How does a cycle begin, for that matter? In fact, does a cycle ever stop? No, life cycles never truly stop but they can be delayed for certain periods of time. Depending on the organism and the surrounding conditions, quiescence can last for days, weeks, months, years - or even thousands of years. Consider certain bacteria, plant seeds, or even animals that hibernate. In fact, apparently, at least 60% of the planet's microbial biomass spends more time immersed in idleness than in action. In a way, this is not surprising given that any biological activity consumes energy - and some far more than others. Take human egg cells. Stalled for years in ovaries, they patiently await the meagre hope of maturing and the even sparser chance of being fertilized. What causes them to stall? Hosts of protein factors which impede, but also protect, crucial enzymes - such as ribosomes for instance. </summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Snowdrops are here. The tips of daffodil shoots are pushing through the soil, and soft grey buds are preparing to burst on the magnolias. These are reminders that Winter marks the end of one life cycle while Spring marks the one about to begin. How does a cycle begin, for that matter? In fact, does a cycle ever stop? No, life cycles never truly stop but they can be delayed for certain periods of time. Depending on the organism and the surrounding conditions, quiescence can last for days, weeks, months, years - or even thousands of years. Consider certain bacteria, plant seeds, or even animals that hibernate. In fact, apparently, at least 60% of the planet's microbial biomass spends more time immersed in idleness than in action. In a way, this is not surprising given that any biological activity consumes energy - and some far more than others. Take human egg cells. Stalled for years in ovaries, they patiently await the meagre hope of maturing and the even sparser chance of being fertilized. What causes them to stall? Hosts of protein factors which impede, but also protect, crucial enzymes - such as ribosomes for instance.</p></b> <div class="quoteleft">« Ribosomes are large complexes of RNA (rRNA) and proteins that carry out crucial activities in every single cell. They are small factories whose end product are proteins. In fact, ribosomes synthesize every single protein an organism needs. When you know that one cell hosts about 42 million proteins - which are also recycled - and that the human body accommodates about 30 trillion cells, you realise that an awful lot of ribosomes are working very hard and, usually, without a break. »</div> <p>Ribosomes are large complexes of RNA (rRNA) and proteins that carry out crucial activities in every single living organism and, largely, every single cell. They are small factories whose end product are proteins. In fact, ribosomes synthesize every single protein an organism needs. When you know that one cell hosts about 42 million proteins - which are also recycled - and that the human body accommodates about 30 trillion cells, you realise that an awful lot of ribosomes are working very hard and, usually, without a break. How do ribosomes synthesize proteins? To cut a very long and complex story short, ribosomes read a cell's genes and, much in the way you follow a recipe, they translate them into proteins. With DNA and RNA, ribosomes are therefore at the very heart of life and its continuation. <p>Infection, lack of food, osmotic stress, temperature shock, gametogenesis are just a few of the circumstances that can trigger off cell dormancy - which is a way of keeping a cell alive with its engine, so to speak, running as low as possible. In dormant cells, ribosomes are stalled because proteins are less in demand. This state of affairs is regulated via protein factors known as dormant factors. Why do cells keep their ribosomes? Why not synthesize new ones when needed? Because the production of new ribosomes costs cells a lot of energy. If existing ribosomes are just shut down for a while, cells only have to trigger them back into action again when necessary. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt277.jpg" alt="snowdrops"/><figcaption>Snowdrops, screenprint by<a href="https://www.annaharley.com/"> Anna Harley </a></figcaption><dd><br></dd> <figcaption>Instagram:<a href="https://www.instagram.com/annaharleyprint/"> @annaharleyprint</a></figcaption><p><p>courtesy of the artist</figure></div> <div class="quoteright">« Infection, lack of food, osmotic stress, temperature shock, gametogenesis are just a few of the circumstances that can trigger off cell dormancy. In dormant cells, ribosomes are stalled because proteins are less in demand. This state of affairs is regulated by dormant factors. Why do cells keep their ribosomes? Why not synthesize new ones when needed? Because the production of new ribosomes costs cells a lot of energy. Triggering existing ones back into action is faster and less costly. »</div> <p>Dormant ribosomes were what molecular biologists James Watson and Alfred Tissières observed in 1958, although they were unaware of it at the time. Cell biologist George Palade was the first to discover ribosomes in 1953, using electron microscopy. Crick and Tissières wanted to know what ribosomes did, so they prepared E.coli cultures - first placing them on ice. This caused a cold shock and the bacteria rapidly shut down their ribosomes. Today, we know that dormant ribosomes tend to aggregate thus forming very large complexes. This is what Crick and Tissières inadvertently observed: ribosomes that were dormant and larger than their natural state. Years later, in the 1970s, snapshots of lizard cells showed ribosomal aggregates set out periodically forming crystalline sheets. This turned out to be a lizard's way of preserving ribosomes while hibernating. So ribosomal dormancy brings about a shift in function as well as in structure - both of which are regulated by dormant factors. <p>How do dormant factors actually affect ribosomes? First we need to understand a ribosome's architecture. Briefly, active ribosomes are made up of two main subunits - a small one and a big one. Each subunit is itself composed of rRNA and many ribosomal proteins that are important for ribosome assembly and function, while the roles of others remain unknown. This combination of rRNA and protein provides crucial active sites that will collaborate to synthesize a protein chain, amino acid by amino acid, supported by hosts of other factors among them initiation factors, elongation factors, termination factors and recycling factors. <p>Protein synthesis is a complex and intricate business. Hence, for the sake of brevity and clarity, a number of (important) steps have been omitted. Ribosomes begin by recognizing and then reading the sequence of a given gene - in the form of messenger RNA (mRNA) which, itself, has been transcribed from the cell's DNA. To do this, the mRNA is held between the ribosome's subunits and shifts to one side as it is read - as well as edited to ensure that the gene is read correctly. Much in the way you would translate Chinese into Arabic, the mRNA sequence is translated into amino acids that are subsequently bound to one another in the order they are read. The nascent protein chain protrudes from a tunnel, known as the polypeptide exit tunnel, situated in the large subunit. Once the ribosome has read the whole gene, the completed protein chain is released. <p>Dormant factors act on ribosomes to repress protein synthesis but also to ensure their preservation. There are many ways of preventing protein synthesis. You can stop ribosomes from initiating mRNA translation. Or you can stop them from adding amino acids to a nascent protein chain. This is exactly what two key dormant factors were found to do in zebrafish and Xenopus eggs: intracellular hyaluronan-binding protein 4 (Habp4) and death-associated protein 1b (Dap1b). Dap1b associates with factors that usually initiate protein synthesis, while Habp4 associates with factors that usually elongate nascent protein chains (and also exists in humans). Both factors act by squatting important active sites. Dap1b inserts its C-terminus into the ribosome's polypeptide exit tunnel placing its fifth-last amino acid exactly where the first amino-acid residue of a nascent protein would lodge - thus blocking the initiation of novel protein synthesis. Habp4, on the other hand, squats the entry of the mRNA tunnel so the ribosome is unable to read and translate mRNA. All in all, Dap1b and Habp4, with the help of initiation and elongation factors, respectively, collaborate to stall protein synthesis while also stabilizing the ribosome for future use. <p>So, depending on the surroundings, cells are able to shift between dormant and non-dormant states relatively fast thanks to hosts of dormant and "re-cycling" factors, respectively. Myriads of factors form multitudes of connections with the ribosomes, protecting their active sites from degradation while putting protein synthesis on hold. Ribosomes are an obvious choice to promote cell dormancy but many other enzymes are also expected to switch to dormant states. Perhaps sets of ribosomes become dormant while others remain active. Perhaps waves of ribosomes are stalled - or re-activated - in a sequential manner. It is an exciting field of research and an emerging one. A field, too, which will help scientists understand how protein synthesis is regulated both in healthy individuals and in disease. </a></em><p><p><div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Leesch F., Lorenzo-Orts L., Pribitzer P., et al.<p> A molecular network of conserved factors keeps ribosomes dormant in the egg<p> Nature 613:712-720(2023)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=36653451&query_hl=3&itool=pubmed_docsum">36653451</a></dd><dd>2. Helena-Bueno K., Chan L.I., Melnikov S.V.<p> Rippling life on a dormant planet: hibernation of ribosomes, RNA polymerases, and other essential enzymes<p> Frontiers in Microbiology (May 2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38770025&query_hl=3&itool=pubmed_docsum">38770025</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Intracellular hyaluronan-binding protein 4, <em>Danio rerio</em> (Zebrafish) <em>(Brachydanio rerio)</em>: <a href="http://www.uniprot.org/uniprot/Q6NRY1">Q6NRY1</a><br></dd><dd>Intracellular hyaluronan-binding protein 4, <em>Xenopus laevis</em> (African clawed frog): <a href="http://www.uniprot.org/uniprot/Q5XJA5">Q5XJA5</a><br></dd><dd>Intracellular hyaluronan-binding protein 4, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q5JVS0">Q5JVS0</a><br></dd><dd>Death-associated protein-like 1 homolog, <em>Danio rerio</em> (Zebrafish) <em>(Brachydanio rerio)</em>: <a href="http://www.uniprot.org/uniprot/Q9I9N0">Q9I9N0</a><br></dd><dd>Death-associated protein-like 1.S, <em>Xenopus laevis</em> (African clawed frog): <a href="http://www.uniprot.org/uniprot/A3KMU5">A3KMU5</a><br></dd>]]> </content></entry> <entry> <title>yellow</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-276.html" /> <id>tag:web.expasy.org,2025:/spotlight//2.940</id> <published>2025-01-23T11:45:01Z</published> <updated>2025-03-25T09:55:54Z</updated> <summary>Chimpanzees use twigs to catch ants. Crows use roads to crack nuts. Humans too have always been good at diverting things for their own benefit - far more than any other species for that matter. We use water to make electricity, cows to provide us with milk and atoms to create heat. With the arrival of biotechnology, the habit has continued. A variety of molecules are now more known for what we do with them than for their original purpose. Green fluorescent protein (GFP) comes to mind - a protein that creates light in jellyfish and, for years now, has been used in research and medicine to label and track molecules and cells. Another is glucose oxidase, or GOx. This enzyme feeds on glucose and oxygen producing hydrogen peroxide in its wake. Since the 1950s, the enzymatic link between these three molecules has provided scientists with a limitless source of inspiration. GOx is currently used to preserve all sorts of consumable items while monitoring their sweetness and warding off microbes. It is also used in medicine to regulate glucose levels in fluids as it is used in the textile industry for bleaching and even in engineering to improve the viscosity of cements. A sort of success story for an enzyme that was discovered exactly 100 years ago.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Chimpanzees use twigs to catch ants. Crows use roads to crack nuts. Humans too have always been good at diverting things for their own benefit - far more than any other species for that matter. We use water to make electricity, cows to provide us with milk and atoms to create heat. With the arrival of biotechnology, the habit has continued. A variety of molecules are now more known for what we do with them than for their original purpose. Green fluorescent protein (GFP) comes to mind - a protein that creates light in jellyfish and, for years now, has been used in research and medicine to label and track molecules and cells. Another is glucose oxidase, or GOx. This enzyme feeds on glucose and oxygen producing hydrogen peroxide in its wake. Since the 1950s, the enzymatic link between these three molecules has provided scientists with a limitless source of inspiration. GOx is currently used to preserve all sorts of consumable items while monitoring their sweetness and warding off microbes. It is also used in medicine to regulate glucose levels in fluids as it is used in the textile industry for bleaching and even in engineering to improve the viscosity of cements. A sort of success story for an enzyme that was discovered exactly 100 years ago.</p></b> <div class="quoteleft">« In 1925, the Danish botanist Detlev Müller was experimenting with the fungus Aspergillus niger when he noticed that bacteria were unable to flourish in its presence. Once glucose was extracted from the preparation, the bacteria grew. This implied that A.niger uses glucose to keep bacteria at bay. Detlev then noticed that when glucose is added to his preparation, oxygen is readily consumed. These observations finally led to his discovery of glucose oxidase, or GOx. »</div> <p>In 1925, a young Danish botanist, Detlev Müller, was experimenting with the fungus <em>Aspergillus niger</em> when he noticed that bacteria were unable to flourish in its presence. He realised that when glucose was extracted from the preparation, the bacteria grew. This implied that <em>A.niger</em> probably uses glucose as a means to keep bacteria at bay. The botanist then noticed that when glucose is added to his preparation, oxygen is readily consumed. These observations finally led to his discovery of glucose oxidase, or GOx. In the presence of glucose, oxygen and water, GOx produces gluconic acid and hydrogen peroxide: glucose + O2 + H2O → gluconic acid + H2O2. It is the hydrogen peroxide that kills off bacteria. <p>So Detlev Müller was the first to discover glucose oxidase. He was also the first to discover flavoproteins though, surprisingly, he seems to have been unaware of this at the time. Flavoproteins are characteristically yellow. This is because they carry cofactors known as flavins which, when oxidised, become yellow - hence their name, from the Latin <em>flavus</em>. GOx is a flavoprotein but Müller never mentions the colour yellow in his writings. Consequently, for many years, the German physiologist Otto Warburg was recognised as the first scientist to have observed a flavoprotein in the 1930s - in his case a respiratory enzyme, glucose 6-phosphate dehydrogenase, in baker's yeast <em>Saccharomyces cerevisiae</em>. Researchers today wonder why Müller omitted to consider the importance of the yellow pigment. Some argue that, as a botanist, he was used to pigments and will have thought that the colour of his precipitate was not significant within the framework of his study. He was interested in how <em>A.niger</em> dealt with bacteria. What he failed to see was that the yellow pigment held what was at the heart of the enzymatic reaction. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt276.jpg" alt="Vincent van Gogh"/><figcaption>A Field of Yellow Flowers</figcaption><dd><br></dd> <figcaption>Vincent van Gogh (1853-1890)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Today, GOx is added to items as diverse as toothpaste and bread dough. It is used to preserve foods and beverages as well as to enhance their colour and keep their flavour. It is used to improve the firmness of breadcrumbs and lower the content of alcohol in wines, as an anti-microbial agent in oral hygiene, as bleach in the textile industry and to add resistance to cement. In the medical field, GOx is used to fight off the growth of cancer cells and monitor the levels of sugar in diabetes. »</div> <p>Despite this, the flavoenzyme Müller unveiled became one of the first enzymes to be used in the field of biotechnology - and the most extensively. Today, GOx is added to items as diverse as toothpaste and bread dough. It is used to preserve foods and beverages as well as to enhance their colour and keep their flavour. It is used to improve the firmness of breadcrumbs and lower the content of alcohol in wines, as an anti-microbial agent in oral hygiene, as bleach in the textile industry and to add resistance to cement. In the medical field, GOx is used to fight off the growth of cancer cells and monitor the levels of sugar in diabetes. Like squeezing the last drops of juice from a lemon, we seem to be extruding from GOx everything we can. <p>It is not difficult to understand why. Each molecule GOx is intimately involved with - glucose, oxygen, water and hydrogen peroxide - is hugely popular in the framework of our planet's chemistry because they are crucial to myriads of biochemical and physicochemical processes. Pop GOx into wine and it will sup up glucose and regulate alcohol content. Add it to foods and it will rid them of the oxygen that makes them turn brown. Introduce it to textiles and the hydrogen peroxide will act as bleach. Insert it into toothpaste and the same peroxide will kill off oral bacteria. Present it to tumours and it will deprive them of energy (glucose) to grow. Couple it with biosensors and it will measure glucose levels in blood. The list seems endless. <p>This is why GOx is known almost inside out today. Extracellular, it belongs to the glucose-methanol-choline oxidoreductase superfamily, where each member depends on the same flavin cofactor: flavin adenine dinucleotide, or FAD. FAD is mainly bound to residues located at the N-terminal of GOx and is at the heart of the enzyme's redox reactions. GOx functions as a dimer. The FAD groups of each monomer meet without binding to one another and nestle down in the apex of a cone-shaped active site that forms at the dimer interface. It seems, too, that a water molecule lodges at the centre of the active site where it forms hydrogen bonds - perhaps conferring a certain stability to the site's overall structure. When glucose is present, it slips down into the cone-shaped active site, possibly displacing the molecule of water as it does. In the cone's apex, thanks to the presence of O2 and to FAD, the glucose substrate is oxidised to produce gluconic acid and hydrogen peroxide. <p>Naturally, it was not for the benefit of humans and their activities that GOx first came to be. To date, this particular flavoenzyme has only been found in fungi and a few insects. As Müller first described, it is used to fend off bacteria by producing hydrogen peroxide (H2O2). Bees actually inject GOx into honey no doubt to check bacteria growth as the nectar ripens. This is why honey is sometimes used to treat chronic wounds and burns. GOx has a fast turnover and high stability which is why it has proved to be so useful in industry and medicine. Though the enzyme has been stripped down to its very bones and thoroughly examined from every angle, no one yet has been able to define the structure of the dimer with its glucose substrate. Understanding how things happen at the active site will undoubtedly widen up a horizon that is already astoundingly vast. Little did Detlev Müller know how far his initial observations would stretch. Nor did he seem to have realised that he was the first to discover flavoproteins. Such is the unexpectedness of research. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Bauer J.A., Zámocká M., Majtán et al.<p> Glucose oxidase, an enzyme "Ferrari": its structure, function, production and properties in the light of various industrial and biotechnological applications<p> Biomolecules 472: (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35327664&query_hl=3&itool=pubmed_docsum">35327664</a></dd><dd>2. Heller A., Ulstrup J.<p> Detlev Müller's discovery of glucose oxidase in 1925<p> Analytical Chemistry 93:7148-7149(2021)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=33904729&query_hl=3&itool=pubmed_docsum">33904729</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Glucose oxidase, <em>Aspergillus niger</em>: <a href="http://www.uniprot.org/uniprot/P13006">P13006</a><br></dd>]]> </content></entry> <entry> <title>unconventional</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-275.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.939</id> <published>2024-12-20T16:25:15Z</published> <updated>2024-12-20T16:57:19Z</updated> <summary>There are about 8 billion people living on our planet today. It's a lot. But consider the following: one human body harbours about 380 trillion viruses and 39 trillion bacteria - both on our skin and underneath it. That means there are thousands of times more organisms living off one of us than there are humans living off the whole Earth. So, as you stroll down a snow-clad path on a crisp and sunny winter's afternoon, thinking how wonderful it sometimes is to be alone, from a purely biological point of view you are not. Your body is literally teeming with organisms that use you as convenient terrain to reproduce, multiply and spread. The great majority of these organisms - viruses, bacteria and fungi - belong to what is called our microbiome. Over the years, we have formed some kind of understanding with our microbiome, and we all get on together fairly well on a give and take basis. As an illustration, the sum of viruses we carry, our virome, is thought to have an overall role in keeping our immune system alert. In this light, scientists recently discovered a novel immune strategy used by our brain cells to prevent the herpes virus from infecting them. The mechanism involves a protein known as TMEFF1.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>There are about 8 billion people living on our planet today. It's a lot. But consider the following: one human body harbours about 380 trillion viruses and 39 trillion bacteria - both on our skin and underneath it. That means there are thousands of times more organisms living off one of us than there are humans living off the whole Earth. So, as you stroll down a snow-clad path on a crisp and sunny winter's afternoon, thinking how wonderful it sometimes is to be alone, from a purely biological point of view you are not. Your body is literally teeming with organisms that use you as convenient terrain to reproduce, multiply and spread. The great majority of these organisms - viruses, bacteria and fungi - belong to what is called our microbiome. Over the years, we have formed some kind of understanding with our microbiome, and we all get on together fairly well on a give and take basis. As an illustration, the sum of viruses we carry, our virome, is thought to have an overall role in keeping our immune system alert. In this light, scientists recently discovered a novel immune strategy used by our brain cells to prevent the herpes virus from infecting them. The mechanism involves a protein known as TMEFF1.</p></b> <div class="quoteleft">« Herpes, or the herpes simplex virus (HSV), is a virus most of us have had close encounters with, more often than not in the form of cold sores. The Roman emperor Tiberius (42BC-37AD) is said to have banned kissing in the capital to stop the spread of such sores, suggesting that HSV has been travelling across the human population for at least 2,000 years. »</div> <p>Herpes, or the herpes simplex virus (HSV), is a virus most of us have had close encounters with, more often than not in the form of cold sores. The Roman emperor Tiberius (42BC-37AD) is said to have banned kissing in the capital to stop the spread of such sores, suggesting that HSV has been travelling across the human population for at least 2,000 years. Thought to have originated in Africa, there is reason to believe herpes is the result of cross-species transmission from apes to humans. Surprisingly, it was only in the 1940s that scientists discovered that cold sores were the doings of a virus. Twenty years later, the first antiviral therapies were introduced, followed by others in the 1970s and the 1980s but to date, despite 30 years of research, no vaccine has been found. <p>There are two kinds of herpes: HSV-1 and HSV-2. HSV-1 affects 64% of the world's population under the age of 50. Usually caught during childhood, it is the main cause of oral herpes, or the common cold sore. HSV-2 is estimated to affect 13% of the world's population aged 15 to 49. It is the main cause of genital herpes and spreads by sexual contact. The maddening thing is our system never gets rid of HSV. The infection is kept at bay but once inside us the virus is there to stay. Following an initial infection in our epithelial cells, HSV gets into nerve cell roots and makes its way up to the sensory nerve ganglia. Here, the virus lies dormant until it is reactivated at a time impossible to predict, but usually when our immune system is not in top form. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt275.jpg" alt="Kamisaka Sekka"/><figcaption>"Kamisaka Sekka (1866-1942)"</figcaption><dd><br></dd> <figcaption>woodcut, 1910</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« HSV-1 is responsible for the rare occurrence of herpes simplex virus encephalitis (HSE) - the most common viral encephalitis in the Western world. HSE is life-threatening and affects about 2 people out of 100,000 individuals per year, especially children between the ages of 3 months and 6 years old. Why is HSV-1 harmful to only un unlucky few? Why is the central nervous system of some individuals more vulnerable to HSV-1? Is there a genetic predisposition? Yes, there seems to be. »</div> <p>HSV-1 is responsible for the rare occurrence of herpes simplex virus encephalitis (HSE) - the most common viral encephalitis in the Western world. HSE is life-threatening and affects about 2 people out of 100,000 individuals per year, especially children between the ages of 3 months and 6 years old. Why is HSV-1 harmful to only un unlucky few? Why is the central nervous system of some individuals more vulnerable to HSV-1? Is there a genetic predisposition? Yes, there seems to be. Unlike other parts of the body, the central nervous system does not cope well with viral infection or a full-blown immune reaction. The blood-brain barrier is usually able to limit the damage as it filters the entry of cellular and molecular components - including those that are part of an immune reaction. However, the brain must also be able to fight off viruses that cross this barrier, naturally. This would then imply that it has different antiviral strategies for its own specific protection. <p>Recently, scientists discovered a protein which happens to be deficient on the surface of brain cortical cells in individuals prone to developing HSE. The protein is called Transmembrane protein with EGF-like and two follistatin-like domains 1, or TMEFF1, and is usually found predominantly on brain cells. Not only does TMEFF1turn out to be involved in countering HSV-1 infection, but it does not depend on classic antiviral immune response such as that triggered off by interferons for example. So TMEFF1 is an immune strategy specific to the central nervous system. How does its presence affect HSV-1? <p>Viruses only infect given cells. The flu virus, like the coronavirus, typically goes for cells in the respiratory tract, for instance, while the polio virus heads straight for brain cells involved in muscle movement. For this, viruses need to recognise specific targets - or receptors - on the surface of the cells they are going to attack. It turns out that HSV-1 specifically recognises the entry receptor Nectin-1 located on the surface of cortical brain cells. Once bound to it, the virus and the brain cell fuse thus initiating infection. Ultimately, HSV-1's DNA is injected into the brain cell nucleus and the host's replication machinery is hijacked to produce viral progeny. Now, if TMEFF1 is also present on the brain cell surface, researchers found out that HSV-1 is unable to bind to Nectin-1 and thus unable to infect the cell. <p>So what does it do? TMEFF1 acts as a restriction factor for HSV-1. A transmembrane protein, the N-terminus of TMEFF1 protrudes into the extracellular medium while its C-terminus dangles in the cell cytoplasm. The N-terminal portion interacts with Nectin-1 in such a way that HSV-1 is unable to bind to it - though, for the time being, no one knows exactly how this happens. Meanwhile, on the cytoplasmic side of the brain cell, the C-terminal portion of TMEFF1 interferes with other factors, namely NMHC-IIA and NMHC-IIB, which usually guarantee viral-cell fusion. Taken together, both actions ensure that HSV-1 has a hard time infecting brain cells. <p>It sounds straightforward, but viral entry always requires myriads of factors that need to cooperate for infection to be successful. In the same way, blocking viral infection also involves many factors. This said, besides the fact that TMEFF1 is something of a free-spirit and does not require activation by other immune factors, it certainly seems to have a pivotal role in stopping HSV-1 infection. It could also explain why people who are deficient for the restriction factor are more liable to suffer from HES. Did TMEFF1 evolve especially to preserve our brain from infection? Perhaps. With this in mind, producing the extracellular domain of TMEFF1 in soluble form could provide therapies to help fight off HSV-1 and perhaps even HSV-2 infections - both in the central nervous system and elsewhere. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Chan Yi-Hao, Liu Zhiyong, Bastard Paul et al.<p> Human TMEFF1 is a restriction factor for herpes simplex virus in the brain<p> Nature 632:390-400(2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39048830&query_hl=3&itool=pubmed_docsum">39048830</a></dd><dd>2. Dai Y., Idorn M., Serrero M.C., et al.<p> TMEFF1 is a neuron-specific restriction factor for herpes simplex virus<p> Nature 632:383-389(2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=39048823&query_hl=3&itool=pubmed_docsum">39048823</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Tomoregulin-1, <em>Homo sapiens </em> (Human): <a href="http://www.uniprot.org/uniprot/Q8IYR6">Q8IYR6</a><br></dd><dd>Tomoregulin-1, <em>Mus musculus </em> (Mouse): <a href="http://www.uniprot.org/uniprot/Q6PFE7">Q6PFE7</a><br></dd>]]> </content></entry> <entry> <title>on dosing and compensating</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-274.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.938</id> <published>2024-11-28T13:37:45Z</published> <updated>2024-12-20T16:45:26Z</updated> <summary>Drosophila flies are born with four pairs of chromosomes in each of their cells. It is the genetic heritage they receive from their genitors. Three of these pairs are simply two versions of the same chromosome, as in two copies of chromosomes 2, 3 and 4. The first pair, however, represents the sex chromosomes - of which there are two, X and Y. Female fruit flies receive an X chromosome from both parents, while male fruit flies receive an X chromosome from their female genitor and a Y chromosome from their male genitor. Just like in humans! In fact, just like all mammals. This is the system Nature uses to produce scores of male and female animals. Now give this a thought: if some fruit flies are XX and others are XY, do the former not have more of something? And the latter something else altogether? For the XY individuals, the answer is yes. That is what makes them male. For the XX individuals, however, the answer is no. Though they may carry an extra X chromosome, in Drosophila, researchers have discovered a protein whose role is to prevent any kind of genetic imbalance with regards, precisely, to X-linked genes. Its name? MSL2.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b><em>Drosophila</em> flies are born with four pairs of chromosomes in each of their cells. It is the genetic heritage they receive from their genitors. Three of these pairs are simply two versions of the same chromosome, as in two copies of chromosomes 2, 3 and 4. The first pair, however, represents the sex chromosomes - of which there are two, X and Y. Female fruit flies receive an X chromosome from both parents, while male fruit flies receive an X chromosome from their female genitor and a Y chromosome from their male genitor. Just like in humans! In fact, just like all mammals. This is the system Nature uses to produce scores of male and female animals. Now give this a thought: if some fruit flies are XX and others are XY, do the former not have more of something? And the latter something else altogether? For the XY individuals, the answer is yes. That is what makes them male. For the XX individuals, however, the answer is no. Though they may carry an extra X chromosome, in <em>Drosophila</em>, researchers have discovered a protein whose role is to prevent any kind of genetic imbalance with regards, precisely, to X-linked genes. Its name? MSL2.</p></b> <div class="quoteleft">« Across all organisms, the expression of one gene over another, or sets of genes over others, is of crucial importance. If the natural balance of gene expression is altered - in other words the production of proteins - it will bring about disorders of some kind, either developmental or disease. The pairing of sex chromosomes is very intriguing because the natural balance of gene expression seems to have been altered from the very start. »</div> <p>Across all organisms, the expression of one gene over another, or sets of genes over others, is of crucial importance. If the natural balance of gene expression is altered - in other words the production of proteins - it will bring about disorders of some kind, either developmental or disease. The pairing of sex chromosomes is very intriguing because the natural balance of gene expression seems to have been altered from the very start. In humans, for example, X and Y do share some identical genes but really very few, barely 5%. The other 95% is unique to Y. So organisms carrying XX and those carrying XY will tend to bear different genetic potentials. How is some kind of balance restored? In <em>Drosophila</em>, for example, the expression of genes on the X chromosome in XY individuals is upregulated. In mammals, yet another dosage compensation system has been adopted. Instead of upregulating the expression of genes on the X chromosome in XY individuals, one X chromosome is inactivated in XX individuals. As a result, X chromosome expression is levelled out for everyone. <p>Gene expression must be one of the most intricate biological processes there is, because there are several hurdles to tackle before it can be done. DNA is a fragile molecule and is therefore highly protected. First, it is preserved in a special cellular compartment: the nucleus. Second, within the nucleus and at regular intervals, the DNA of each chromosome is coiled around multitudes of identical protein structures, or histones, much in the manner fishermen coil ropes around moors. This histone-DNA structure then coils further to create very tightly-packed chromatin (DNA and histones). This is wonderful for protecting DNA but it does not make things easy when cells need to express genes and make proteins. In order to access the DNA, cells need to unwind coils and set aside histones. Also, though we will go into no detail, besides targeting the right gene and binding to it, they still have to split apart the stable double helix to transcribe only one side of it. Needless to say, gene expression involves hordes of different proteins, enzymes and cofactors - all of which interact at various stages. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt274.jpg" alt="Paul Klee"/><figcaption>"Tight Rope Walker (1923)"</figcaption><dd><br></dd> <figcaption>by Paul Klee (1879-1940)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Gene expression must be one of the most intricate biological processes there is, because there are several hurdles to tackle before it can be done. DNA is highly protected. First, it is preserved in a special cellular compartment: the nucleus. Second, within the nucleus, the DNA of each chromosome is stored in tightly-packed chromatin. This is wonderful for protecting DNA but it does not make things easy when cells need to express genes and make proteins. »</div> <p>So, in terms of dosage compensation, how do we understand the upregulation of an X chromosome in male <em>Drosophila</em>? It all has to with a complex that has been called the Male Specific Lethal (MSL) complex. MSL complex is an assembly of five protein dimers (MSL1, MSL2, MSL3, MLE and MOF) and two non-coding RNAs (ncRNA) - each of which have specific roles, such as structural, chromatin interactions, protein-protein interactions, DNA-binding and the like. In <em>Drosophila</em>, the MSL complex assembles exclusively in male (XY) flies where it acts on the X chromosome. There, it begins by modifying (acetylating) the histones around which DNA is coiled. This action opens up the overall chromatin structure, paving the way for gene expression. The MSL complex then binds to specific sites, High Affinity Sites (HAS), scattered along the X chromosome DNA. Bouncing from HAS to HAS, the MSL complex gradually coaxes the increased expression of X-linked genes. <p>You may be wondering, do female <em>Drosophila</em> have MSL complexes? Yes, proteins that are part of the complex are also found in female flies. However, the expression of one of its subunits - protein MSL2 - is inhibited. This not only saves female flies from the unleashed overexpression of their X chromosomes, but it must also mean that MSL2 has a central role in chromosome upregulation in male flies. MSL2 is activated when it binds to MSL1 via its RING domain - a domain composed of seven cysteine residues which coordinate two zinc atoms. Tethered to the MSL complex, MSL2 then pulls it from HAS to HAS as it binds to DNA via its CXC domain - a nucleic acid binding domain made up of a cluster of nine cysteine residues that coordinate another three zinc atoms. <p>This is how upregulation of the male <em>Drosophila</em> X chromosome is explained. MSL complexes also exist in mammals. Similar in their composition and assembly, they are also active in dosage compensation but not in the same circumstances. In mammals, the MSL complex does not upregulate the X chromosome in XY individuals since another system silences one of the X chromosomes in XX individuals. So what does it do? The mammalian MSL complex seems to be crucial in the event of haploinsufficiency. What does this mean? Humans receive two copies of each gene: one from our mother, the other from our father. These are called alleles. As described implicitly above, both alleles are usually expressed. A gene is haplo-insufficient when one of its alleles is inactive. In such instances, the MSL complex can be called up to activate the silenced allele, much in the way the complex upregulates the X chromosome in <em>Drosophila</em>. In mammals, the MSL complex thus retains the same role but uses it for a different purpose. Again, MSL2 is a key protein in the process but its exact role is unknown. It could be that MSL2 frees space on chromatin by preventing protective DNA methylation or perhaps heightening histone acetylation like in <em>Drosophila</em>, thus giving transcription factors the chance to reach genes. <p>Gene expression is a fascinating field of research. Silencing genes while activating others is what gives rise to an intrinsic and vital biological balance every single organism depends on. Here we have the example of a protein, or a set of proteins - the MSL complex - that evolution has retained over time. But not quite for the same purpose. Although it always involves the upregulation of gene expression, the circumstances in which it occurs is not the same. In <em>Drosophila</em>, the MSL complex upregulates the expression of genes on the X chromosome in XY individuals. In mammals, it seems to have been kept to upregulate the expression of alleles that have been silenced so as to restore bi-allelic expression. Loss of MSL2 can lead to developmental disorders such as eye malformation, or brain and kidney defects. So getting to know how it works in full molecular detail would help to develop novel therapies. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Sun Y., Wiese M., Hmadi R. et al.<p> MSL2 ensures biallelic gene expression in mammals<p> Nature 624: (2023)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38030723&query_hl=3&itool=pubmed_docsum">38030723</a></dd><dd>2. Keller C.I., Akhtar A.<p> The MSL complex: juggling RNA-protein interactions for dosage compensation and beyond<p> Current Opinion in Genetics & Development 31:1-11(2015)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=25900149&query_hl=3&itool=pubmed_docsum">25900149</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>E3 ubiquitin-protein ligase msl-2, <em>Drosophila melanogaster </em> (Fruit fly): <a href="http://www.uniprot.org/uniprot/P50534">P50534</a><br></dd><dd>E3 ubiquitin-protein ligase msl-2, <em>Homo sapiens </em> (Human): <a href="http://www.uniprot.org/uniprot/Q9HCI7">Q9HCI7</a><br></dd><dd>E3 ubiquitin-protein ligase msl-2, <em>Mus musculus </em> (Mouse): <a href="http://www.uniprot.org/uniprot/Q69ZF8">Q69ZF8</a><br></dd>]]> </content></entry> <entry> <title>shift</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-273.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.937</id> <published>2024-10-29T10:25:57Z</published> <updated>2024-12-04T09:55:19Z</updated> <summary>When humans migrated from Africa to other parts of the globe, they carried with them a certain set of genes. Over the many thousands of years that have passed since, a good deal of these genes have been subjected to minor or perhaps major changes as our ancestors adapted - by the grace of natural selection - to their new environments. One such gene is ACTN3 that produces a protein known as α-actinin-3, itself an integral part of muscle. About 20 years ago, researchers discovered, quite by chance, that many humans - an estimated 1.5 billion today! - have no α-actinin-3 at all in their muscle. Yet they are perfectly healthy individuals. The researchers also observed that humans who had no α-actinin-3 had greater endurance, while those who did sport the protein were usually good sprinters. The absence or presence of α-actinin-3 in muscle depends on a specific mutation whose effect can actually change the nature of muscle fibre. This may have been a consequence of adapting to colder climates, but the side effects are fortunate for athletes: either they have the ability to run far effortlessly or the skill to run a short distance fast.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>When humans migrated from Africa to other parts of the globe, they carried with them a certain set of genes. Over the many thousands of years that have passed since, a good deal of these genes have been subjected to minor or perhaps major changes as our ancestors adapted - by the grace of natural selection - to their new environments. One such gene is ACTN3 that produces a protein known as α-actinin-3, itself an integral part of muscle. About 20 years ago, researchers discovered, quite by chance, that many humans - an estimated 1.5 billion today! - have no α-actinin-3 at all in their muscle. Yet they are perfectly healthy individuals. The researchers also observed that humans who had no α-actinin-3 had greater endurance, while those who did sport the protein were usually good sprinters. The absence or presence of α-actinin-3 in muscle depends on a specific mutation whose effect can actually change the nature of muscle fibre. This may have been a consequence of adapting to colder climates, but the side effects are fortunate for athletes: either they have the ability to run far effortlessly or the skill to run a short distance fast.</p></b> <div class="quoteleft">« An estimated 18% of the human population have no muscle α-actinin-3, yet they are all healthy individuals. Lacking α-actinin-3 may provide resilience to the cold thanks to muscle-generated heat - which could explain why humans migrating to colder climates gradually shed their α-actinin-3 simply to keep warm. The mutation has come with unexpected side effects: elite athletes who carry α-actinin-3 are usually good sprinters, while those who have no α-actinin-3 have greater endurance. »</div> <p>Exactly twenty years ago, a team of researchers discovered that the absence of an important muscle fibre protein in individuals, α-actinin-3, has no pathogenic effect. Probably because an isoform of α-actinin-3, α-actinin-2, was acting as a substitute. More surprising, perhaps, was the find that an estimated 18% of the human population have no α-actinin-3 at all - which would imply some kind of evolutionary benefit. It turns out that the lack of α-actinin-3 provides resilience to the cold thanks to muscle-generated heat - which could explain why humans migrating to colder climates gradually shed their α-actinin-3 simply to keep warm. And the mutation has come with unexpected side effects: elite athletes who carry α-actinin-3 are usually good sprinters, while those who have no α-actinin-3 have greater endurance. <p>Muscles are very organised tissues that are composed of muscle cells, or muscle fibres, of which there are two kinds: fast fibres and slow fibres. These two fibres differ, mainly, in their number of mitochondria and myoglobin. Each muscle fibre is a tightly packed bundle of fibrils, or myofibrils. Myofibrils are, themselves, an intricate assembly of two major proteins: myosin and actin that support muscle contraction - although interactions with myriads of other proteins are necessary for muscle integrity and metabolism too. Among these: α-actinins. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt273.jpg" alt="Cyril Power"/><figcaption>"The Runners (ca. 1930)"</figcaption><dd><br></dd> <figcaption>linocut by Cyril Power (1872-1951)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« In the absence of α-actinin-3, muscle fibres turn to the more efficient aerobic (oxidative) pathway to produce energy - a pathway usually preferred by slow fibres. So there is a shift from fast fibre properties to slow fibre properties without a structural change of the fibre itself! How can this happen? It may have to do with glycogen metabolism. »</div> <p>α-actinins are a very ancient family of proteins, possibly predating the divergence of eukaryotes and prokaryotes, which is thought to have occurred about 3 billion years ago. This just goes to show how crucial α-actinins must be for living organisms. For years, scientists thought that α-actinins had a purely structural role in muscle. This is because they were first observed bridging actin filaments in myofibrils in a zone known as the Z band. Much like in Lego, myofibrils are an assembly of contractile units called sarcomeres. The zone where one sarcomere meets another, and that can be visualized as a disc, is the Z band. It is here that α-actinins stretch from one actin filament to another to anchor them while stabilising the overall muscle apparatus. Over the years, however, it has become apparent that α-actinins have more than just a structural role: they are also involved in signalling and metabolic pathways during muscle contraction. <p>There are various α-actinins but α-actinin-3 seems to be the most specialised and is found only in fast fibres in skeletal muscle. Like all α-actinins, α-actinin-3 has a distinctive domain structure. It begins with an N-terminal actin-binding domain (ABD), followed by a central rod made up of a varied amount of repeats (Sel1-like repeats or SLRs), and a C-terminal domain that contains two EF hand regions (an EF hand is said to resemble a stretched out forefinger and thumb, with a clenched middle finger). α-actinin-3 monomers bind via their central rod repeats to form active antiparallel dimers. The formation of head to tail dimers has two important consequences. First, both ends are capable of binding to an actin filament. Secondly, within the same dimer, the N-terminal end of one α-actinin-3 monomer can interact with the C-terminal end of the other. This is important since α-actinin-3 is believed to be at the heart of several important pathways in skeletal muscle, and not only to form a stable sarcomeric lattice. <p>So what happens when α-actinin-3 is deficient? First of all, α-actinin-2 can step in and do its job. However, a total lack of α-actinin-3 does modify the overall behaviour of the muscle fibre. α-actinin-3 is only found in fast fibres. Fast fibres rely on an anaerobic pathway to produce the energy muscles need (ATP) to contract. In the absence of α-actinin-3, the fibres turn to the more efficient aerobic (oxidative) pathway to produce energy - a pathway usually preferred by slow fibres. So there is a shift from fast fibre properties to slow fibre properties without a structural change of the fibre itself! How can this happen? It may have to do with glycogen metabolism. Fast fibres rely on a readily available source of glycogen to supply energy. When α-actinin-3 is deficient, it could be that the key enzyme glycogen phosphorylase, which is involved in glycogen breakdown, is altered to favour an oxidative pathway. Moreover, glycogen phosphorylase has been reported to interact with α-actinins. <p>So switching from fast fibre type to slow fibre type will have helped our ancestors resist cold as they migrated northwards - and perhaps even famine. Unknown to them, of course, was the change this shift brought about in muscle function with respect to physical performance. α-actinin-3 deficiency in individuals reduces their ability to use muscle glycogen as a source of energy for muscle contraction. This would, in turn, reduce their ability to generate the energy they need for power sports. This said, an athlete's performance not only depends on their genetic makeup but also on environmental parameters such as diet and training. It did not take long for ACTN3 to join the growing list of genetic markers associated with athletic performance. But this does not, in any way, deprive us of what ACTN3 represents in the field of molecular evolution. Here we have a protein which, in a way, seems to have become redundant though what it has really done is step aside so that our ancestors could survive in a hostile environment. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Lee F.X.Z., Houweling P.J., North K.N., Quinlan K.G.R.<p> How does α-actinin-3 deficiency alter muscle function? Mechanistic insights into ACTN3, the 'gene for speed'<p> Biochimica et Biophysica Acta 1863:686-693(2016)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=26802899&query_hl=3&itool=pubmed_docsum">26802899</a></dd><dd>2. MacArthur D.G., North K.N.<p> A gene for speed? The evolution and function of α-actinin-3<p> BioEssays 26:786-795(2004)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15221860&query_hl=3&itool=pubmed_docsum">15221860</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Alpha-actinin-3, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q08043">Q08043</a><br></dd><dd>Alpha-actinin-3, <em>Mus musculus</em> (Mouse): <a href="http://www.uniprot.org/uniprot/O88990">O88990</a><br></dd>]]> </content></entry> <entry> <title>cutting edges</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-272.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.936</id> <published>2024-10-18T08:35:57Z</published> <updated>2024-10-22T09:21:09Z</updated> <summary>Things may appear different to you depending on how you look at them - or at which angle you approach them. What you will make of them will also depend on what you already know about them. This is true for people as it is for any problem you may have undertaken to solve. Take plasma membrane rupture (PMR), for instance. In PMR, a cell's membrane is breached so that its insides seep out and the cell, unable to repair its membrane faster than it is damaged, gradually dies. PMR is not a passive event but brought about by a protein known as NINJ1. A name which may ring a bell for some readers, and rightly so. Early on in the year, I wrote about the role this protein has in creating rips in cell membranes. So why write about NINJ1 again? Because it is intriguing to see how the understanding of a given biological mechanism can change depending on the data that is available. Today, a second team of scientists suggests that NINJ1 does not just cause slits in the plasma membrane but rather cuts out holes, much in the way you would cut out shapes with a cutter in biscuit dough. </summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Things may appear different to you depending on how you look at them - or at which angle you approach them. What you will make of them will also depend on what you already know about them. This is true for people as it is for any problem you may have undertaken to solve. Take plasma membrane rupture (PMR), for instance. In PMR, a cell's membrane is breached so that its insides seep out and the cell, unable to repair its membrane faster than it is damaged, gradually dies. PMR is not a passive event but brought about by a protein known as NINJ1. A name which may ring a bell for some readers, and rightly so. Early on in the year, I wrote about the role this protein has in creating rips in cell membranes. So why write about NINJ1 again? Because it is intriguing to see how the understanding of a given biological mechanism can change depending on the data that is available. Today, a second team of scientists suggests that NINJ1 does not just cause slits in the plasma membrane but rather cuts out holes, much in the way you would cut out shapes with a cutter in biscuit dough.</p></b> <div class="quoteleft">« Today, scientists have accepted the notion that cells die to preserve life but the understanding of Programmed Cell Death is now as complex and intricate as an electronic board. Cells die in different ways, provoked by different pathways, and each way has been given a name like pyroptosis, necroptosis, ferroptosis or apoptosis - each involving interactions of various factors to give rise to maze-like pathways that leave you utterly befuddled. »</div> <p>The concept of programmed cell (PCD) death took quite some time to be acknowledged by biologists. Currently, however, not only have we wholly accepted the notion that many of our - or any living organism's - cells die to preserve life but the understanding of PCD has now become as complex and intricate as an electronic board. We have discovered that cells, die in different ways, provoked by different pathways, and each way has been given a name like pyroptosis, necroptosis, ferroptosis or apoptosis - each involving interactions of various factors to give rise to maze-like pathways that leave you utterly befuddled. Relief comes when you learn that whichever path the cell chooses, the very last step seems always to be tackled by NINJ1 whose ultimate job is to puncture the cell's membrane. How exactly NINJ1 does this is precisely what is under debate. <p>One team of researchers<sup>2</sup> suggests that NINJ1 monomers assemble to create transmembrane fence-like structures that slit the cell's membrane; this was discussed in a previous article*. A second team<sup>1</sup>, which we consider here, suggests that NINJ1 monomers assemble into transmembrane ring-like structures that cut out a hole in the cell's membrane exactly in the way a cutter would cut out a shape in biscuit dough. The difference in interpretation comes from the data that was available to each research team, and their consequent understanding of NINJ1's 3D structure. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt272.jpg" alt="multicolor acrylic dots"/><figcaption>Multicolor Acrylic Dots by<a href="https://kikasworkshop.com/"> Erika C. Brothers </a></figcaption><dd><br></dd> <figcaption>Instagram:<a href="https://www.instagram.com/ecbrothers/"> @ecbrothers </a></figcaption><p><p>courtesy of the artist</figure></div> <div class="quoteright">« Is it really important to know how a cell is punctured if the outcome is the same, you may wonder? From a certain perspective, perhaps not. However, a slit is not the same as a pit, and the instruments used to create each must differ somehow too. Also, from a purely biological point of view, whether NINJ1 oligomers form curved or straight filaments, this is a wonderful illustration of how the 3D structure of a protein is at the heart of what defines its function - one of biology's paradigms. »</div> <p>Both teams agree that active NINJ1 monomers are a chain of two C-terminal transmembrane helices (α3 and α4) and two N-terminal smaller helices (α1 and α2). The two larger helices fold over to lie side by side. The two smaller helices form a right-angle with each other, and α2 binds parallel to transmembrane helix α3 while α1 reaches out, so to speak, to bind to another NINJ1 monomer. In this way, the active monomers form filaments. Where the two teams differ in interpretation stems from the shape of the filaments they observed. The first team concluded that the filaments formed oligomers whose backbone was straight. This led them to believe that NINJ1's transmembrane segment, formed by α3 and α4, was also straight. The second team, however, observed curved filaments - and this led them to suggest that the transmembrane segment of NINJ1 was not straight but kinked. Indeed, each helix - both α3 and α4 - seems to bend at the precise location of a glycine residue. As a result, the helices adopt a kind of molecular spoon hug. <p>According to the second team of researchers, this spoon hug conformation would give rise to curved filaments, or ring segments, something the team actually observed. A given number of ring segments could then join to form a complete ring-like structure. Moreover, each ring segment presents a convex and a concave side which, prior to activation, are both hydrophobic by nature. Upon NINJ1 activation, that is to say upon α1 and α2 insertion, the inner concave side of the ring would remain hydrophobic while the convex side becomes hydrophilic. To put things simply, the inner part of the ring would remain bound to cell membrane, while the outer hydrophilic edge would sever itself from it. So we have the biscuit cutter. <p>Is it really important to know how a cell is punctured if the outcome is the same, you may wonder? Is it really of interest to know that a cell dies because it is riddled with rips, or pierced all over with holes? From a certain perspective, perhaps not. However, a slit is not the same as a pit, and the instruments used to create each must differ somehow too. The knowledge of how exactly NINJ1 oligomers perform to cause cellular disintegration could open up therapeutic opportunities in the field of cancer, infection and inflammatory diseases for example. Alternatively, from a purely biological point of view, whether NINJ1 oligomers form curved or straight filaments, this is a wonderful illustration of how the 3D structure of a protein is at the heart of what defines its function - one of biology's paradigms.<p>* <em><a href="https://www.proteinspotlight.org/back_issues/265/"> Protein Spotlight issue 265: Rupture </a></em><p><p><div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. David L., Borges J.P., Hollingsworth L.R. et al. <p> NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks<p> Cell 187:2224-2235(2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38614101&query_hl=3&itool=pubmed_docsum">38614101</a></dd><dd>2. Degen M., Santos J.C., Pluhackova K. et al. <p> Structural basis of NINJ1-mediated plasma membrane rupture in cell death<p> Nature 618: (2023)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=37198476&query_hl=3&itool=pubmed_docsum">37198476</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Ninjurin-1, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q92982">Q92982</a><br></dd><dd>Ninjurin-1, <em>Mus musculus</em> (Mouse): <a href="http://www.uniprot.org/uniprot/O70131">O70131</a><br></dd>]]> </content></entry> <entry> <title>liquid yellow</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-271.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.935</id> <published>2024-08-14T10:56:49Z</published> <updated>2024-08-15T10:05:45Z</updated> <summary>When the opportunity to write a piece on urine arose, I thought "wonderful, here's something we can all relate to". I had no idea, however, where it was going to lead me: from Hippocrates, uroscopy and the tradition of Hebridean waulking to alchemy, quacks and The Pisse Prophet, a 17th century satire. Very early on, physicians took a keen interest in what each one of us exudes at least twice a day. Gradually, urine became a sort of medical manual per se in which the overall state of health of its host could simply be read - so much so that physicians began to feel that it was unnecessary to even meet their patients. Still today, urine tests help doctors form their diagnoses, but they certainly do not exclude carrying out other tests or talking to their patients. Urine has many tales to tell - depending on its colour, its scent, its molecular composition. In healthy individuals, it is usually a shade of pale yellow owing to the yellow pigment found in it: urobilin. Urobilin is just another component of the total waste product that forms urine and whose presence depends on an enzyme of bacterial origin: biliverdin reductase.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>When the opportunity to write a piece on urine arose, I thought "wonderful, here's something we can all relate to". I had no idea, however, where it was going to lead me: from Hippocrates, uroscopy and the tradition of Hebridean waulking to alchemy, quacks and The Pisse Prophet, a 17th century satire. Very early on, physicians took a keen interest in what each one of us exudes at least twice a day. Gradually, urine became a sort of medical manual per se in which the overall state of health of its host could simply be read - so much so that physicians began to feel that it was unnecessary to even meet their patients. Still today, urine tests help doctors form their diagnoses, but they certainly do not exclude carrying out other tests or talking to their patients. Urine has many tales to tell - depending on its colour, its scent, its molecular composition. In healthy individuals, it is usually a shade of pale yellow owing to the yellow pigment found in it: urobilin. Urobilin is just another component of the total waste product that forms urine and whose presence depends on an enzyme of bacterial origin: biliverdin reductase.</p></b> <div class="quoteleft">« Humans have always put to good use the most surprising things. Our ancestors, for example, used urine in several inventive ways. It became a fertiliser while also being used to make gunpowder - and fireworks for that matter. In preindustrial times, urine-derived ammonia, was used as a cleaning fluid and a mordant for textile dyes. In the Hebrides, woven wool was actually soaked in urine... »</div> <p>Urine, and its excretion, is one of the many ways humans - like so many other animals - have of ridding their bodies of chemicals and molecules that are uninvited or no longer welcome. It is, in a way, a by-product of an organism's overall metabolism, besides being one of the most conspicuous. Unsurprisingly, urine is mainly water while the rest, barely 10%, is composed of inorganic salts, a lot of urea - which is full of nitrogen - as well as myriads of other organic compounds and ammonium salts, with a sprinkling of protein, hormones, metabolites and toxins. It really all depends on what you have ingested and what is going on inside you. <p>Humans have always had this way of putting to good use many things which may seem basic to us today - such as using yeast in the process of brewing beer or making bread. In this way, our ancestors made use of urine in several inventive ways. It soon became a fertiliser, where the nitrogen infiltrates the soil and is pumped back into the life cycle. It was used to make gunpowder, which sounds utterly incongruous. How? Left to rot on straw, the water evaporated, leaving in its wake crystals of potassium nitrate (saltpetre crystals) which form the greater part of what is needed to make gunpowder - and fireworks for that matter. In preindustrial times, urine-derived ammonia, whose smell we know so well, was used as a cleaning fluid and a mordant for textile dyes. In the Hebrides, woven wool was soaked in urine, though preferably an infant's. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt271.jpg" alt="Lila Copeland"/><figcaption>"Stephen peeing"</figcaption><dd><br></dd> <figcaption>etching by Lila Copeland (1912-?)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Urine is a filtrate of the blood, processed by our kidneys. Its colour depends on the presence of urobilin, a yellow pigment, which occurs following the normal ageing and destruction of red blood cells. In blood, urobilin exists in the form of bilirubin, which is then reduced to urobilinogen which oxidises spontaneously to give, ultimately, the yellow pigment. »</div> <p>Physicians, too, were swift to realise that urine could perhaps reveal what was going on inside us. In fact, urine marks the very beginnings of laboratory medicine which is thought to have emerged with the Sumerians about 6000 years ago - although it is the Greek physician Hippocrates who is credited with being the founder of uroscopy, i.e. the inspection of urine. As the centuries rolled on, uroscopy gradually became the most acclaimed diagnostic tool - to the extent of flirting with the absurd, perhaps even proving to be dangerous. An accurate diagnosis depended on the shape of the vessels in which urine was collected. Some physicians believed that different parts of the vessel echoed different parts of the human body. Charts emerged describing up to twenty types of urine related to different bodily ailments. Some physicians even thought it redundant to talk to a patient. By the 17th century, there were so many 'pisse-prophets' and 'pissemongers' that the British physician Thomas Brian published The Pisse Prophet, a satirical text which ridiculed the ongoing practice of uroscopy. The science subsequently lost its aura. In came urinalysis, as we know it today. <p>Urine is a filtrate of the blood, processed by our kidneys. Its colour depends on the presence of urobilin, a yellow pigment that was discovered over a century ago. However, until recently, scientists did not know how this pigment was actually synthesized. Urobilin occurs following the normal ageing and destruction of red blood cells. Red blood cells carry oxygen around our bodies thanks to chemical compounds known as haems that are an integral part of haemoglobin. Urobilin is a direct product of haem degradation. In the blood, it exists in the form of bilirubin. Bilirubin is then reduced to urobilinogen which oxidises spontaneously to give urobilin - the yellow pigment. <p>Are enzymes responsible for these changes? Yes. One in particular: biliverdin reductase, or BilR. BilR belongs to the Old Yellow Enzyme (OYE) family so named in the 1930s. Why old? Because a second "new" yellow enzyme was found shortly after the first. Why yellow? Because the enzyme's cofactor is a yellow pigment: flavin mononucleotide (FMN). Bilirubin reductases have motifs (HGDR motifs) which are exclusive to them. These particular reductases are thought to be the key step in haem degradation, deciding which haem by-products are reabsorbed and which are excreted. BilR acts on bilirubin by reducing multiple carbon-carbon double bonds. Surprisingly, the enzyme is expressed not by us but by microorganisms that belong to our microbiome, namely Clostridia of the phylum Firmicutes. In fact, this particular bacterium is itself solely responsible for the reduction of bilirubin to urobilinogen. Hence: for the colour of our pee. <p>All in all, BilR activity, or haem excretion, is an essential function of the healthy human gut. Then, surely, its presence or its absence is indicative of certain diseases, or at least of a body's homeostasis. Indeed, infants who suffer from jaundice shortly after birth seem to lack BilR. This may be because their microbiome is not yet fully developed. Levels of BilR in patients suffering from inflammatory bowel disease (IBD) are also low which demonstrates that the enzyme is essential for the balance of important metabolites. The level of BilR in urine is thus indicative of a patient's state of health and can help to pin down certain diseases. BilR, however, is also present in bacteria found in water and in soil, suggesting that the enzyme breaks down bilirubin - or metabolites similar to it - in environments other than human gut. A notion which would have surely inspired a uroscopist or two. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Hall B., Levy S., Dufault-Thompson K., et al.<p> BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen<p> Nature Microbiology 9:173-184(2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38172624&query_hl=3&itool=pubmed_docsum">38172624</a></dd><dd>2. Armstrong J.A.<p> Urinalysis in Western culture: A brief history<p> Kidney International 71:384-387(2007)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17191081&query_hl=3&itool=pubmed_docsum">17191081</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Biliverdin reductase, <em>Clostridioides difficile</em> (strain CD3): <a href="http://www.uniprot.org/uniprot/P0DXD0">P0DXD0</a><br></dd>]]> </content></entry> <entry> <title>nausea</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-270.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.934</id> <published>2024-07-11T12:12:33Z</published> <updated>2024-08-14T11:28:45Z</updated> <summary>Food poisoning is an ordeal. The body empties itself, with no respite, until nothing is left - neither vitality in you nor food in your system. It is less a single food item you have ingested which causes the unpleasant experience than the poison that was lurking in the smoked salmon, or the oyster, or the steak tartare you helped yourself to. Though we tend to curse our system when it happens, we should in fact be encouraging it. Why? Because it has sensed an ingested toxin that could be harmful to us. The fastest and most effective way of dealing with the toxin is to rid us of everything we have eaten. It so happens that a similar phenomenon occurs in the majority of pregnant women. During the first months of pregnancy, nausea hits many women the moment they rise in the morning or smell certain foods, or drink, during the course of the day. Though disagreeable to say the least, it is thought to be both for the mother's and the developing child's good. Indeed, morning sickness, as it is commonly known, could be linked to the potential ingestion of detrimental toxins, and to the presence of a protein known as GDF15.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Food poisoning is an ordeal. The body empties itself, with no respite, until nothing is left - neither vitality in you nor food in your system. It is less a single food item you have ingested which causes the unpleasant experience than the poison that was lurking in the smoked salmon, or the oyster, or the steak tartare you helped yourself to. Though we tend to curse our system when it happens, we should in fact be encouraging it. Why? Because it has sensed an ingested toxin that could be harmful to us. The fastest and most effective way of dealing with the toxin is to rid us of everything we have eaten. It so happens that a similar phenomenon occurs in the majority of pregnant women. During the first months of pregnancy, nausea hits many women the moment they rise in the morning or smell certain foods, or drink, during the course of the day. Though disagreeable to say the least, it is thought to be both for the mother's and the developing child's good. Indeed, morning sickness, as it is commonly known, could be linked to the potential ingestion of detrimental toxins, and to the presence of a protein known as GDF15.</p></b> <div class="quoteleft">« Morning sickness usually lasts for the first three months of pregnancy - though it may stretch further. It so happens that during this time the foetus is at its most vulnerable while developing two of its most important organs: the heart and the brain. The mother, too, is less protected as her immune system has been weakened to ensure that her child - much like an organ transplant - is not rejected. »</div> <p>Morning sickness, also known as 'nausea and vomiting of pregnancy' (NVP), usually lasts for the first three months of pregnancy. More precisely: from the fourth to the sixteenth week, though it may stretch further. It so happens that during this time the foetus is at its most vulnerable while developing two of its most important organs: the heart and the brain. The mother, too, is less protected as her immune system has been weakened to ensure that her child - much like an organ transplant - is not rejected. The majority of pregnant women, as many as 70%, suffer from NVP. So, surely, there must be a reason for it. Does it, for that matter, not also exist in other mammals? In the 1990s, scientists suggested that NVP probably occurs to protect the mother and the child from toxins that could be damaging. In a way, it is Mother Nature's way of ensuring her legacy. Either toxins have actually been ingested, or the feeling of nausea keeps the mother away from items susceptible to contain any. If this is indeed the origin of NVP, though perhaps not elegant, the result is certainly simple and effective. <p>In the recent past, scientists discovered a protein whose level in the blood of pregnant mothers can increase hugely - sometimes dramatically. More intriguing, perhaps, is the find that the protein is mainly - but not exclusively - of foetal origin. Known as growth differentiation factor 15, or GDF15, the protein is normally present in many tissues in humans - male or female. It seems to be expressed when our bodies are subject to a form of stress and is thought to have a protective role of some kind, to such an extent that is has been dubbed the 'survival protein', though its exact role has yet to be unveiled. In fact, over the years, the protein's involvement in such a diverse array of biological functions has had it baptised MIC-1, NAG-1, PTGFB, PDF, PLAB... However, in the light of protection against toxins, GDF15 and pregnancy make utter sense. The foetus seems to pump GDF15 into its mother's blood to ensure its own protection while ensuring the mother's too - in a sort of win-win situation. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt270.jpg" alt="Carl-Albert Angst"/><figcaption>Carl-Albert Angst (1875-1965)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Recently, scientists discovered a protein (GDF15) whose level in the blood of pregnant mothers can increase hugely - sometimes dramatically. More intriguing, perhaps, is the find that the protein is mainly, although not exclusively, of foetal origin. It seems to be expressed when our bodies are subject to a form of stress and is thought to have a protective role of some kind. »</div> <p>GDF15 is a protein hormone. It belongs to the transforming growth factor beta (TGFβ) superfamily that plays vital roles in embryonic development, cellular homeostasis, cellular growth, cellular adhesion, cellular migration, cellular proliferation and apoptosis - although GDF15, itself, diverges from the other members of the superfamily by the number of cysteine residues in its sequence. The N-terminus of the protein is long (about 200 amino acids) and necessary for the correct folding of the active hormone (about 100 amino acids long), which is active once dimerized. GDF15 may exist in three different forms in the cell, i.e. as 1) a pro-GDF15 monomer, 2) a pro-GDF15 dimer, and 3) the mature active homodimer which is subsequently secreted. The inactive pro-GDF15 monomer is thus roughly 300 amino acids long. Its C-terminal contains cysteine residues which link to a second pro-GDF15 monomer to create the inactive pro-GDF15 dimer. It seems that both the inactive pro-GDF15 dimer and the active form are secreted. However, pro-GDF15 dimer binds to the extracellular matrix where it is stored while the active GDF15 dimer is released into the circulation. <p>Back to morning sickness. Although GDF15 is naturally present in humans, we now know that its occurrence increases in most pregnant women and is mainly of foetal origin. In fact, the severity of NVP seems to be linked to how sensitive the mother is to the protein hormone GDF15. This sensitivity depends on the amount of GDF15 naturally present in mothers when non-pregnant. In short, if women have relatively high levels of GDF15 in their blood when they are not expecting a child then they will probably suffer from NVP which, from a purely biological point of view, is a good thing. It so happens that a more severe form of NVP exists - coined hyperemesis gravidarum, or HG. Women who suffer from HG (about 2% of pregnancies) are unable to eat or drink normally and end up losing weight, which can complicate pregnancy. However, although HG can prove to be violent and some women have to be hospitalized, the foetus suffers no harm. It is believed that HG is probably caused by the presence of a specific isoform of GDF15. On the other hand, women who have relatively high levels of GDF15 in their blood when non-pregnant seem to be less at risk of developing HG. <p>As a protein hormone, GDF15 binds to receptors to trigger off downstream signalling pathways in cells. What pathways does GDF15 promote? How does it work? Does it bind to more than one receptor? Present in many tissues, its role is still poorly defined but it has been found to be involved in many different instances: obesity, diabetes, cardiometabolic disease, ageing, neurodegenerative disease, NVP, appetite, cancer... Consequently, GDF15 is expected to bind to a variety of receptors. What we know for sure today, however, is that GDF15 binds to a receptor known as GDNF family receptor α-like protein, or GFRAL, which is only expressed in the hindbrain. In fact, GDF15 binds to a heterodimer of GFRAL and a protein kinase receptor known as RET, and it is this bond that is ultimately responsible for morning sickness, or what scientists call 'aversive responses'. <p>One question arises: why do most women feel much better after the first trimester of pregnancy? This is now quantitively explained by a net drop in the presence of GDF15 in their blood. But what about safety? Naturally, the embryo - now a foetus - is less vulnerable but not completely out of harm's way. However, the foetus now needs all the energy it can get to continue its development, and this fact may well outweigh that of producing GDF15 and the risk of possible poisoning or infections. The fluctuating rate of GDF15 in a mother's blood and her susceptibility to NVP or HG is intriguing. Perhaps mothers who are diagnosed as prone to HG - or to violent bouts of NVP - could be sensitized to GDF15 before becoming pregnant. This would avoid taking drugs which may lessen the symptoms but could probe to be harmful to the child. We only have to think of the antiemetic thalidomide tragedy (see protein spotlight issue 117) in the late 1950s and early 1960s which caused thousands of miscarriages in many countries, and as many children born with deformities that were more or less severe - and continue to be so today. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Fejzo M., Rocha N., Cimino I., et al.<p> GDF15 linked to maternal risk of nausea and vomiting during pregnancy<p> Nature 625: (2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38092039&query_hl=3&itool=pubmed_docsum">38092039</a></dd><dd>2. Assadi A., Zahabi A., Hart R.A.<p> GDF15, an update of the physiological and pathological roles it plays: a review<p> European Journal of Physiology 472:1535-1546(2020)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=32936319&query_hl=3&itool=pubmed_docsum">32936319</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Growth/differentiation factor 15, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q99988">Q99988</a><br></dd>]]> </content></entry> <entry> <title>a motherly mesh</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-269.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.933</id> <published>2024-05-24T11:24:25Z</published> <updated>2024-05-24T11:38:40Z</updated> <summary>Toxic waste. Since the 19th century, our species has had to find ways of scrapping industrial detritus which is frequently dangerous. So, we dig deep down into the earth and leave the nasty stuff there or we build thick crusts of cement around it. We then count on time to do the rest. Cells also produce refuse which, unless degraded or somehow set aside, will end up by being harmful to them. So they, too, have devised ways of dealing with it - namely with all kinds of degradative systems lodged within the cells themselves. Some cells, however, are not able to get rid of their scrap material in a timely fashion. Take oocytes, for example. Most mammalian oocytes are arrested at a certain developmental stage as they await ovulation - which may take several decades. During this rather long period, oocytes are kept in a sort of lethargic state and are unable to deal with degradation. So how do they cope with their waste? The answer is ELVAs, or endo-lysosomal vesicular assemblies. Much like fishnets, ELVAs trap noxious scrap within a proteinaceous mesh whose formation is initiated by a protein known as RUFY1.</summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Toxic waste. Since the 19th century, our species has had to find ways of scrapping industrial detritus which is frequently dangerous. So, we dig deep down into the earth and leave the nasty stuff there or we build thick crusts of cement around it. We then count on time to do the rest. Cells also produce refuse which, unless degraded or somehow set aside, will end up by being harmful to them. So they, too, have devised ways of dealing with it - namely with all kinds of degradative systems lodged within the cells themselves. Some cells, however, are not able to get rid of their scrap material in a timely fashion. Take oocytes, for example. Most mammalian oocytes are arrested at a certain developmental stage as they await ovulation - which may take several decades. During this rather long period, oocytes are kept in a sort of lethargic state and are unable to deal with degradation. So how do they cope with their waste? The answer is ELVAs, or endo-lysosomal vesicular assemblies. Much like fishnets, ELVAs trap noxious scrap within a proteinaceous mesh whose formation is initiated by a protein known as RUFY1.</p></b> <div class="quoteleft">« How humans are made has been debated for thousands of years. The beginnings of an answer truly began to emerge in the 1660s when Melchisedec Thévenot, a French patron of the sciences, asked two of his protégés - Niels Stenson from Denmark and Jan Swammerdam from the Netherlands - to find out what it is in animals that gives rise to other animals. By the 1670s, after many dissections, experiments and discussions, Stenson suggested that all animals come from eggs, and that eggs are also found in women. »</div> <p>How humans are made has been debated for thousands of years. The beginnings of an answer truly began to emerge in the 1660s when Melchisedec Thévenot, a French patron of the sciences, asked two of his protégés - Niels Stenson from Denmark and Jan Swammerdam from the Netherlands - to find out what it is in animals that gives rise to other animals. By the 1670s, after many dissections, experiments and discussions, Stenson suggested that all animals come from eggs, and that eggs are also found in women. It so happens that another student, the Dutch physician Rainier de Graaf, reached the same conclusion at about the same time. He, however, was the first to publish his results. Somewhat ruffled, Swammerdam promptly published his own understanding of the issue - and both men asked the Royal Society to judge which of the two had priority over the theory. <p>Much to their amazement, no doubt, the Royal Society (UK) told them that neither of them had priority. According to the Society's understanding, it was Niels Stenson who had been the first to say that animals come from eggs. Despite this, the history of biology has written things down differently and a follicle - the cellular aggregation in which nests an egg cell - is known today as a Graafian follicle. By the time the decision was taken, and perhaps disappointed by the outcome of things, Niels Stenson had left the realm of science to become a bishop of the Catholic Church - and no one knows if he was ever told about what had been going on. In any event, by the 1670s, scientists had accepted the notion that women store eggs in their ovaries. Although it took another 150 years for the German naturalist Karl Ernst von Baer to actually observe one, in 1827. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt269.jpg" alt="Jessica Dismorr"/><figcaption>Jessica Dismorr (1885-1939)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« ELVAs are sort of liquid super organelles, which, like fishing nets, adopt no particular shape while trapping noxious protein aggregates in their wake. The net is made up of microfilaments, a proteinaceous matrix, to which the degradative organelles bind and in which the aggregates are caught. »</div> <p>Oocytes are one of these rare cells that are long-lived - unlike spermatozoa, their male counterparts, which are created on the spot, when they are needed and from puberty onwards. Girls are born with their a life's stock of oocytes. Dependent first on sexual maturity and then monthly ovulation, the "chosen" oocytes have to survive at least one decade before they get a chance to mature and ovulate. In humans, most of them will have lived for two decades, if not three or even four, before they get the rare opportunity to be fertilised. This is a very long time for one cell to survive, especially as - like any other cell - mal-formed or damaged proteins accumulate forming aggregates that, unless degraded, become harmful. These protein aggregates form in the cell's cytoplasm, and it is crucial that an oocyte's cytoplasm remains healthy since it contains all an embryo needs for the very first divisions. Why, you might be thinking, do oocytes not degrade these aggregates as they form? Much in the way other cells do? That is because, before ovulation, oocytes are kept in a sort of low energy-cost state, and degradative organelles, such as lysosomes, are energy-consuming. So protein aggregates are left to accumulate. <p>Researchers recently observed that mouse oocytes ensure that harmful protein aggregates accumulate in guarded places, i.e. endo-lysosomal vesicular assemblies, or ELVAs. ELVAs are super organelles which have no distinct boundary and are scattered throughout the oocyte's cytoplasm. They can be compared to a fishing net in which are trapped not fish but degradative organelles such as endo-lysosomes, autophagosomes and proteasomes - and also protein aggregates. The organelles are not bound to one another but to a filamentous net. Upon ovulation, when the oocyte matures, the ELVAs migrate - some of them merging into one another as they do so - to the egg's cortex. At the same time, the degradative organelles are activated and the protein aggregates are cleared. By the time an embryo has reached its two-cell stage, no protein aggregates are left. Possibly because they are dangerous for the embryo's development but also because they may provide the embryo with raw building material, such as amino acids. <p>ELVAs are sort of liquid super organelles, which, like fishing nets, adopt no particular shape while trapping protein aggregates in their wake. The net is made up of microfilaments, a proteinaceous matrix, to which the degradative organelles bind and in which the aggregates are caught. Researchers discovered a protein that is directly involved in forming ELVAs: a protein known as the RUN and FYVE domain-containing protein 1, or RUFY1. RUFY1 has three distinct structural domains: an N-terminal RUN domain which is required for membrane association, a central coil-coiled domain which is needed for self-assembly, and a C-terminal domain which binds phosphatidylinositol 3-phosphate, necessary for the protein's activity. RUFY1 is known to be an effector protein which self-assembles and is involved in the formation of early endosomes. In the case of ELVAs, RUFY1 seems to initiate and drive the formation of the proteinaceous matrix to create a kind of biological glue, the net, which holds everything together: both the degradative organelles and protein aggregates. <p>It is a wonderful solution for a situation that, at one point, is bound to become critical for a long-lived cell. Oocytes have developed a way to remain in a state which does not cost them too much energy while stashing away harmful molecules that form as they await maturation - at which point they will have the wherewithal to deal with their waste, while also providing material as they break it down. Discoveries such as these could help scientists understand certain forms of infertility and why some embryos do not reach the two-cell stage. Could it be because the oocyte's noxious aggregates have not all been cleared? Perhaps. Certainly, the more you learn about life and how it is organised, the more you are amazed at how it manages to keep a very fragile - yet sturdy - balance as it tiptoes along a pretty slim tightrope. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Zaffagnini G., Cheng S., Salzer M. et al.<p> Mouse oocytes sequester aggregated proteins in degradative super organelles<p> Cell 187:1109-1126 (2024)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=38382525&query_hl=3&itool=pubmed_docsum">38382525</a></dd><dd>2. Gosden R., Lee B.<p> Portrait of an oocyte: our obscure origin<p> The Journal of Clinical Investigation 120:973-983(2010)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=20364095&query_hl=3&itool=pubmed_docsum">20364095</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>RUN and FYVE domain-containing protein 1, <em>Mus musculus</em> (Mouse): <a href="http://www.uniprot.org/uniprot/Q8BIJ7">Q8BIJ7</a><br></dd>]]> </content></entry> <entry> <title>mouths, enemies and spit</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-268.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.932</id> <published>2024-04-22T17:54:37Z</published> <updated>2024-04-22T18:22:12Z</updated> <summary>Our mouths are teeming with inhabitants of the most diverse origin. Bacteria and fungi for one, but all sorts of various-sized peptides too, each of which carry out various tasks. In fact, our mouths are like a metropolis, with its underlying complexity of continuous bonds and exchanges between its individuals and compartments. As in any society, things need to be kept balanced and regulated to avoid unrest and chaos. Likewise, the bacteria and fungi that nestle down in the nooks and crannies of our mouths must not be left to multiply unrestrained, which would only bring about a full-blown infection. This is why Nature has provided our saliva with an assortment of antimicrobial peptides, just in case things get out of hand. Histatins are antimicrobial peptides found in primate saliva. One histatin, called histatin 5 or Hst5, specifically fights off infections by Candida albicans, a yeast naturally harboured in our mouths. Hst5 does this by using crossing - unscathed - the yeast's membrane to reach the cell's cytoplasm. Hst5 then goes on to meddle with the yeast's ion homeostasis, gradually leading it to its death. </summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Our mouths are teeming with inhabitants of the most diverse origin. Bacteria and fungi for one, but all sorts of various-sized peptides too, each of which carry out various tasks. In fact, our mouths are like a metropolis, with its underlying complexity of continuous bonds and exchanges between its individuals and compartments. As in any society, things need to be kept balanced and regulated to avoid unrest and chaos. Likewise, the bacteria and fungi that nestle down in the nooks and crannies of our mouths must not be left to multiply unrestrained, which would only bring about a full-blown infection. This is why Nature has provided our saliva with an assortment of antimicrobial peptides, just in case things get out of hand. Histatins are antimicrobial peptides found in primate saliva. One histatin, called histatin 5 or Hst5, specifically fights off infections by <em>Candida albicans</em>, a yeast naturally harboured in our mouths. Hst5 does this by using crossing - unscathed - the yeast's membrane to reach the cell's cytoplasm. Hst5 then goes on to meddle with the yeast's ion homeostasis, gradually leading it to its death.</p></b> <div class="quoteleft">« Though C.albicans can survive on its own, many of us carry the yeast around in the lining of our mouths, our genitourinary tract and on our skin, without it causing much trouble - or us them for that matter. However, when our immune system is weakened, C.albicans can switch into an aggressive mode and multiply, ultimately infecting our cells. Most of the time, infections are kept at bay. Occasionally, however, they become invasive, spreading to other parts of our body - sometimes even causing death. »</div> <p><em>Candida albicans</em> is a commensal yeast, meaning it is a eukaryotic cell that is happy to share its life with another species. In particular, it likes to spend time with humans because its ideal growth temperature is 37°C. Consequently, though <em>C.albicans</em> can survive on its own, many of us carry the yeast around in the lining of our mouths, our genitourinary tract and on our skin, without it causing much trouble - or us them for that matter. However, when feeling under the weather or stressed, or in a situation where our immune system is weakened, <em>C.albicans</em> can switch into an aggressive mode and multiply, ultimately infecting our cells. Most of the time, infections are kept at bay. Occasionally, however, they become invasive, spreading to other parts of our body - sometimes even causing death. <p>Secreted by glands situated in our mouths, our saliva is stashed with components which each have a purpose. There are those needed for lubrification, those required for cleaning or for digestion, those that are vital for creating protective barriers and those that are called up for self-defence. Over 200 proteins and peptides are estimated to make up our saliva but there is also a lot of water, minerals and metals - all of which interact with each other to create a very lively environment. Our saliva is so rich with peptides that scientists have divided them into different families, depending on their composition mainly. Among these peptides are histatins - so named because they are full of the amino acid histidine. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt268.jpg" alt="Hinko Smrekar"/><figcaption>Hinko Smrekar (1883-1942)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Histatins emerged as important factors of our immune system when their capacity to fight off yeast infection was discovered. This finding coincided with the AIDS outbreak in the 1980s when immunocompromised patients suffered from Candida infection. One histatin can be singled out: the metal-binding histatin 5. Not only is Hst5 one of our saliva's major peptide components but also the most potent with regards to antifungal activity. »</div> <p>Histatins are involved in maintaining the soundness of our mouths, such as the enamel on our teeth for instance, by forming a protective pellicle on the smooth surface. They emerged as important factors of our immune system when their capacity to fight off yeast - and to a lesser extent bacterial - infection was discovered. This finding coincided with the AIDS outbreak in the 1980s when immunocompromised patients suffered from <em>Candida</em> infection - an ailment known as thrush. In these patients, histatins were unable to perform their usual microbicidal activity. There are about a dozen histatin family members, each generated from a parent histatin and all structurally related. One histatin can be singled out: the metal-binding histatin 5 (Hst5) cleaved from its parent histatin Hst3. Hst5 is not only one of our saliva's major peptide components but also the most potent with regards to antifungal activity. <p>Histatins are small in size, varying between 7 and 38 amino-acid residues. Like many other antimicrobial peptides (AMPs), the composition of histatins is amphipathic - meaning that they have a head and a tail which have opposite charges. Lipids that form the lipid bilayer of cell membranes are made in the same way. This is no coincidence since, thanks to their similar amphipathic structure, AMPs can slip into cell membranes, locally rearranging the membrane's make-up to create harmful pores, for example, or to facilitate their entry into the host's cytoplasm. Which is exactly how Hst5 enters <em>C.albicans</em>. Though its mechanism of action is not yet fully understood, we know that Hst5 crosses the yeast's cell wall and then its membrane to finally reach the cytoplasm. Here, Hst5 meddles with the flux of ATP, ultimately causing the cell's vital energy to flow out. At the same time, Hst5's capacity to bind metals - such as copper, zinc, iron, nickel, calcium and magnesium - produces intracellular reactive oxygen species (ROS) which, among other things, can damage the yeast's DNA. Taken together, the outflow of ATP and the production of ROS end up killing the yeast cell. <p>Why is it that Hst5 is so free to cross the yeast's membrane? You would expect its passage to be more difficult. You would also expect Hst5 to be degraded the moment it enters the host cell. The thing is, Hst5 is probably recognised as a familiar polyamine by transporters that are lodged in the yeast cell membrane. Hst5 can then simply steal a polyamine's seat and hitch a ride into the cell. Besides the loss of cellular ATP that follows, scientists discovered that there was also an outflow of K+ ions - which only contributes more to the dysregulation of the yeast's global homeostasis. How are K+ ions lost? Polyamines are known to modulate the passage of potassium through potassium channels. Perhaps Hst5 takes over by blocking or opening these channels, thereby dysregulating the flow of intracellular K+. On the other hand, by binding to the channels, Hst5 could distort them in such a way that larger anions, such as ATP, can leak through. So far, it is only a model - albeit an elegant one. <p>AMPs are thought to have been around for about 2.6 billion years - long before the human species was even thought of - which, when considering the complexity of the human immune system for instance, is one of the reasons they are so "crude" in a way. Despite their crudeness, the moment AMPs were discovered, researchers saw their biomedical potential, and many are currently used in medicine to combat infections. What about antibiotics you may ask? Antibiotics continue to be used, naturally. However, microbes are becoming more and more resistant to them, which is why scientists are looking for alternative solutions. Fine-tuning AMPs is one. As an illustration, depending on the metal Hst5 binds, it behaves differently. Would it not be possible then to influence Hst5's activity by modulating its interactions with metals? No doubt. The thing is, <em>C.albicans</em> is a eukaryotic cell - like all human cells. If you change the nature of Hst5, it may make them harmful to other microbes - which is good - but it could also become harmful to our own cells too. It is all a question of balance. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Vieira Silva Zolin G., Henrique de Fonseca F., Reis Zambom C., Santesso Garrido S.<p> Histatin 5 metallopeptides and their potential against <em>Candida albicans</em> pathogenicity and drug resistance<p> Biomolecules - doi: 10.3390/biom11081209<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=34439875&query_hl=3&itool=pubmed_docsum">34439875</a></dd><dd>2. Kumar R., Chadha S., Saraswat D. et al.<p> Histatin 5 uptake by <em>Candida albicans</em> utilizes polyamine transporters Dur3 and Dur31 proteins<p> Journal of Biological Chemistry 286:43748-43758 (2011)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=22033918&query_hl=3&itool=pubmed_docsum">22033918</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Histatin-3, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/P15516">P15516</a><br></dd>]]> </content></entry> <entry> <title>seizure</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-267.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.931</id> <published>2024-03-26T11:04:52Z</published> <updated>2024-03-26T11:30:18Z</updated> <summary>Many years ago, I was sitting opposite a man whose body suddenly froze. His eyes seemed to be staring at something on the wall behind me while his left hand drew small circles in the air, repetitively. I had no idea what was happening to him until he came back to his senses and told me that he had just had an epileptic fit. Deeply embarrassed, he got up and left the room. Many of us will have witnessed a close relative, a friend, an acquaintance or perhaps simply a passerby, under the influence of an epileptic seizure - which are frequently more violent and alarming than the one I experienced that day. Epilepsy affects millions of people worldwide. However, what is happening on the molecular scale remains elusive. What we do know is that an epileptic fit is caused by neural activity that has suddenly gone out of control. In this light, researchers discovered two tarantula venom peptides - Aa1a and Ap1a - which inhibit channels that are used to relay signals in our central nervous system. Peptides such as these could perhaps be used to keep abnormal neural activity at bay in people suffering from epilepsy. </summary> <author> <name>Vivienne Baillie Gerritsen</name> </author> <category term="Article" scheme="http://www.sixapart.com/ns/types#category" /> <content type="html" xml:lang="en-us" xml:base="https://web.expasy.org/spotlight/"> <![CDATA[<p><b>Many years ago, I was sitting opposite a man whose body suddenly froze. His eyes seemed to be staring at something on the wall behind me while his left hand drew small circles in the air, repetitively. I had no idea what was happening to him until he came back to his senses and told me that he had just had an epileptic fit. Deeply embarrassed, he got up and left the room. Many of us will have witnessed a close relative, a friend, an acquaintance or perhaps simply a passerby, under the influence of an epileptic seizure - which are frequently more violent and alarming than the one I experienced that day. Epilepsy affects millions of people worldwide. However, what is happening on the molecular scale remains elusive. What we do know is that an epileptic fit is caused by neural activity that has suddenly gone out of control. In this light, researchers discovered two tarantula venom peptides - Aa1a and Ap1a - which inhibit channels that are used to relay signals in our central nervous system. Peptides such as these could perhaps be used to keep abnormal neural activity at bay in people suffering from epilepsy.</p></b> <div class="quoteleft">« When witnessing an epileptic fit, the first thing that comes to mind is that something has gone very wrong with the control of our body. In fact, we have no control over it anymore, as though the system for transmitting signals to and from our brain has suddenly gone haywire. Epilepsy is indeed the result of a gross imbalance between neural activation and deactivation. Something our body is unable to cope with. So, it temporarily loses hold. »</div> <p>Until at least the 17th century, epileptic fits were thought to have a divine origin, or be caused by evil spirits. Even though, two thousand years earlier, the Greek physician Hippocrates had rejected the idea that epilepsy had anything to do with spirits but was a problem that stemmed directly from the brain and could be medically treated. Nonetheless, for a very long time after his death, the only kind of healing offered was spiritual, and many suffering from epilepsy were shunned by society, if not interned. Still today, there are societies where epilepsy is believed to be associated with evil spirits, witchcraft or poisoning - and even sometimes considered contagious. <p>Defined as a disease of the brain, epilepsy seems to have a strong genetic predisposition although it can also occur in patients who have suffered brain trauma for example. When witnessing an epileptic fit, the first thing that comes to mind is that something has gone very wrong with the control of our body. In fact, we have no control over it anymore, as though the system for transmitting signals to and from our brain has suddenly gone haywire - which is exactly the case. Epilepsy is the result of a gross imbalance between neural activation and deactivation. Something our body is unable to cope with. So, it temporarily loses hold. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt267.jpg" alt="Otto Freundlich"/><figcaption>KOMPOSITION 1939</figcaption><dd><br></dd> <figcaption>by Otto Freundlich (1878-1943)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« For decades now, scientists have been singling out venom peptides with therapeutic potential. In the case of epilepsy, a well-chosen toxin could perhaps counter the irrational and uncontrolled opening and closing of channels in the central nervous system (CNS), by guaranteeing some kind of regulation. So they scanned the venom of tarantulas and extracted two toxins: both of which are potent inhibitors of specific channels in the CNS. »</div> <p>Neural activation and deactivation depend on the seamless coordination of the opening and closing of channels scattered throughout the central nervous system. The sum of concerted channel activation and deactivation allows us to remain in relative control of our mobility - but also of many other less tangible functions such as consciousness for instance. When channel concertation fails, there is an abnormal surge of neural excitation resulting in an epileptic seizure. A voltage-gated potassium channel known as hEAG is important for human cognitive development. Scientists know this because mutated forms of hEAG give rise to syndromes known as Temple-Baraitser and Zimmermann-Laband, both of which result in mental retardation. Patients also happen to suffer from epilepsy - and this gave researchers the opportunity to understand the matter better. <p>With this in mind, animal venom is constituted of toxins, several of which specifically target channels involved in neural activation and deactivation. What better way to neutralize predators or prey than to meddle with their central nervous system by disrupting essential metabolic pathways that cause temporary paralysis - as the aggressor makes a run for it - or perhaps even death. For decades now, scientists have been singling out venom peptides that could have some kind of therapeutic potential. In the case of epilepsy, which is caused by the irrational and uncontrolled opening and closing of channels, a well-chosen toxin could perhaps counter this by guaranteeing some kind of regulation. So scientists scanned the venom of tarantulas, namely: Avicularia aurantiaca and Avicularia purpurea. The choice was far from innocent since the venom of both tarantulas is known to inhibit hEAG. Two peptides were extracted - kappa-theraphotoxin-Aa1a (Aa1a) from A.aurantiaca, and mu/kappa-theraphotoxin-Ap1a (Ap1a) from A.purpurea - both of which turned out to be potent hEAG inhibitors. <p>Aa1a and Ap1a are 81% identical, consisting of 36 residues with an amidated C-terminus and three disulfide bridges. Their singularity lies in the structure formed by the three bridges: a cystine knot. Imagine a loop formed by two of the bridges, and the third slides through it. This forms a cystine knot - in our case, an inhibitor cystine knot. Cystine knots are relatively common in venom toxins because they confer chemical stability and resistance to enzymatic degradation, which means they can survive for a long time inside the victim. It is perhaps one of the rare times in life when the formation of a knot - whatever its nature - is not deemed a nuisance. Besides the cystine knot, there is another intriguing formation: a sort of ladder whose rungs are formed by the stacking of hydrophobic patches on one side of each inhibitor peptide. These molecular rungs may be necessary to form interactions with the target channel as well as the lipid membrane of brain cells. Certainly, molecular ladders such as these are frequently found in spider toxins whose role is to modify voltage-gated channels. <p>It is likely that Aa1a and Ap1a act by binding to the extracellular regions of hEAG where they cause a depolarising shift in the cell's membrane, reducing the probability that the channel opens by as much as 50%. In short, Aa1a and Ap1a do not deactivate the channels by blocking the central pore, for example, but inhibit them by exerting pressure, so to speak, on the pore domain. Of the two inhibitor peptides, Ap1a is the most potent inhibitor of hEAG, which makes it a potential candidate for the development of anti-epileptic drugs. Indeed, epilepsy affects as many as 70 million people worldwide - of all ages. Although seizures are always short-lived, there are invisible side-effects such as neurobiological and cognitive consequences but also psychological and sociological repercussions. Naturally, there are already many anti-epileptic drugs on the market. However, they are ineffective in as much as one third of persons suffering from recurrent bouts of epilepsy. The more scientists understand about the channels that are responsible for this widespread affliction, the better their knowledge will be to design drugs that will help everyone. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Ma L., Chin Y.K.Y., Dekan Z. et al.<p> Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target<p> Biochemical Pharmacology 158:60-72(2018)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=30149017&query_hl=3&itool=pubmed_docsum">30149017</a></dd><dd>2. Cázares-Ordoñez V., Pardo L.A.<p> Kv10.1 potassium channel: from the brain to the tumors<p> Biochemistry and Cell Biology 95:531-536(2017)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=28708947&query_hl=3&itool=pubmed_docsum">28708947</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Potassium voltage-gated channel subfamily H member 1, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/O95259">O95259</a><br></dd><dd>Kappa-theraphotoxin-Aa1a, <em>Avicularia aurantiaca</em> (Yellow-banded pinktoe tarantula): <a href="http://www.uniprot.org/uniprot/A0A3F2YLP5">A0A3F2YLP5</a><br></dd><dd>Mu/kappa-theraphotoxin-Ap1a, <em>Avicularia purpurea</em> (Ecuadorian purple pinktoe tarantula): <a href="http://www.uniprot.org/uniprot/P0DQJ6">P0DQJ6</a><br></dd>]]> </content></entry> </feed> If you would like to create a banner that links to this page (i.e. this validation result), do the following:
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