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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>2024-04-22T18:22:12Z</updated> <subtitle>one month, one protein</subtitle> <generator uri="http://www.sixapart.com/movabletype/">Movable Type Pro</generator> <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> <entry> <title>fierce</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-266.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.930</id> <published>2024-02-16T12:07:01Z</published> <updated>2024-02-20T13:28:04Z</updated> <summary>Scents communicate. Wrapped in silence perhaps, yet they have much to say. They may revolt us or delight us, go unnoticed or do nothing for us, but scents always have something to convey. So much so that many of us dab a little perfume on the nape of our neck or spray eau de toilette on our torso at the start of each day. We want to smell nice, or at the very least clean. We may even splash a little scent on before going out with an end to seduce. Much like flowers do. Who has not crossed a room or a lawn to inhale the wonderful perfume released by hyacinths, lilacs or a fragrant rose? Or leaned over to breathe in the delicate scent of jasmine wafting from a cup of tea? Long before humans, plants grasped the advantage of releasing pleasant volatile vibes to attract a pollinator or two. Some viruses have caught on with the practice too - and in a rather cunning way. The cucumber mosaic virus, for instance, is capable of infecting plants while also forcing them to become attractive to insects who will transfer the virus to other plants. Uncharacteristically, one sole protein in CMV can perform both actions. Its name is 2b, or CMV2b.</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>Scents communicate. Wrapped in silence perhaps, yet they have much to say. They may revolt us or delight us, go unnoticed or do nothing for us, but scents always have something to convey. So much so that many of us dab a little perfume on the nape of our neck or spray eau de toilette on our torso at the start of each day. We want to smell nice, or at the very least clean. We may even splash a little scent on before going out with an end to seduce. Much like flowers do. Who has not crossed a room or a lawn to inhale the wonderful perfume released by hyacinths, lilacs or a fragrant rose? Or leaned over to breathe in the delicate scent of jasmine wafting from a cup of tea? Long before humans, plants grasped the advantage of releasing pleasant volatile vibes to attract a pollinator or two. Some viruses have caught on with the practice too - and in a rather cunning way. The cucumber mosaic virus, for instance, is capable of infecting plants while also forcing them to become attractive to insects who will transfer the virus to other plants. Uncharacteristically, one sole protein in CMV can perform both actions. Its name is 2b, or CMV2b.</p></b> <div class="quoteleft">« Our vegetable gardens fight vicious battles. So does farmland across the world. CMV has been reported on every single continent, including Antarctica, which is hardly surprising given the range of its hosts: over 1200 plants, including crops and ornamental flowers. Moreover, CMV is transmitted by over 80 different aphid species some of which are able to survive harsh winters, huddled around the roots of their hosts - it is enough to see your backyard greenfly in a different light. »</div> <p>Cucumber mosaic virus has a capsid which is almost spherical in shape. It was characterised for the first time, in 1934, in cucumbers that presented mosaic patterns on their skin - hence the name. However, besides cucumbers, CMV has since shown that it can infect an astounding variety of plants, around the globe. This is more than any other known plant virus can do, and it causes huge damage to crops of all sorts, and subsequent economic loss to farmers. One of the reasons is that the virus is particularly infectious, as it is transmitted via plant sap or simply by insects that happen to land on the plants - or are attracted to them - and unknowingly become vectors. <p>Over time, plants have developed different strategies to fight off viral infection. In the case of CMV, each viral capsid carries three strands of RNA which, upon infection, are released into the plant host. RNA entry triggers off the machinery which ultimately results in viral multiplication. Consequently, one of the host's choice strategies is to attack the viral RNA and degrade it - thus slowing down viral replication or, with any luck, putting an end to it. This strategy is known as post-translational gene silencing, or PTGS. In the model plant Arabidopsis thaliana, PTGS is triggered off by a lipid-based plant hormone known as jasmonate, or jasmonic acid. As its name infers, jasmonate was originally extracted from jasmine oil in the 1960s, itself derived from the jasmine flower which releases the sweet scent we know and that we have worn as perfume since its introduction to Europe in the 16th century. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt266.jpg" alt="Sarah Kirby"/><figcaption>"Pythouse Kitchen Garden" by<a href="https://sarahkirby.co.uk/"> Sarah Kirby </a></figcaption><figcaption>instagram:<a href="https://www.instagram.com/sarahkirbyprint/"> @sarahkirbyprint</a></figcaption><dd><br></dd><figcaption>linocut, courtesy of the artist</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« When CMV infects a plant, the virus uses its host's machinery to synthesize all the proteins it needs to multiply. One of these proteins is CMV2b, which then adopts one of two roles: either it stops the plant's capacity to degrade viral RNA, or it gets the plant to send out signals that attract vectors, such as aphids, which will carry the virus further. »</div> <p>Jasmonate is a plant hormone vital to an indispensable signalling cascade involved in key processes in plants: the jasmonate signalling pathway. This signalling pathway is governed by jasmonate-zim domain (JAZ) proteins, all of which are repressors. There are twelve known JAZ repressors (JAZ1-12) in A.thaliana, each independently active in processes as varied as plant growth, plant development, plant survival, plant regeneration and responses to various kinds of stress. It is this signalling pathway that CMV has - very astutely - chosen to dabble with by way of one of its proteins: cucumber virus protein 2b, or CMV2b. <p>CMV2b is a modest-sized protein which is thought to act as a homotetramer. When CMV infects a plant, the virus uses its host's machinery to synthesize all the proteins it needs to multiply. One of these proteins is CMV2b, which then adopts one of two roles: either it stops the plant's capacity to degrade viral RNA, or it gets the plant to send out odour signals that attract vectors, such as aphids, which will carry the virus further. How does CMV2b do this? Does it have two different functions? Or does the same action result in two different fates? The answer is: CMV2b performs both functions independently. <p>On the one hand, CMV2b can switch off a cell's ability to degrade viral RNA. Consequently, the cell's machinery continues to translate viral RNA which, unless checked, will give rise to progeny. It is not yet known how this occurs on the molecular level but there is reason to believe that CMV2b enters the cell nucleus to interfere directly with DNA methylation - a process involved in the regulation of gene expression. On the other hand, CMV2b can hijack the plant's jasmonate signalling pathway and get it to attract aphids - a major insect pest of many kinds of vegetables, among which the cucumber of course. How does CMV2b manage this? By binding directly to JAZ1, one of the major repressor proteins in the jasmonate signalling pathway. What CMV2b does is take the place of a factor known as COI1 whose role is to degrade JAZ1 thus setting the signalling pathway off. However, when CMV2b takes the place of COI1, JAZ1 is not degraded and thus continues to repress the jasmonate signalling pathway - in other words, the plant's defence system. As a result, no volatiles are released to warn the surrounding plants of viral infection. Instead, aphids are literally able to sniff out the infected plants and are drawn to them. Via their stylet, they then suck the plant's sap, picking up the virus as they do so and transmitting it to any other plant they choose to feed on. <p>It may not seem the case but our vegetable gardens fight vicious battles. So does farmland across the world. CMV has been reported on every single continent, including Antarctica, which is hardly surprising given the range of its hosts: over 1200 plants, including crops and ornamental flowers. Moreover, besides vectors other than aphids, CMV is transmitted by over 80 different aphid species some of which are able to survive harsh winters, huddled around the roots of their hosts - it is enough to see your backyard greenfly in a different light. Certainly, CMV sounds invincible. A greater understanding of the jasmonate signalling pathway and in particular how CMV has found ways to manipulate it, could provide insight for future anti-pest strategies in agriculture. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Wu D., Qi T., Li W.-X. et al.<p> Viral effector protein manipulates host hormone signaling<p> Cell Research 27:402-415 (2017)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=28059067&query_hl=3&itool=pubmed_docsum">28059067</a></dd><dd>2. Li C., Xu M., Cai X. et al.<p> Jasmonate Signaling Pathway Modulates Plant Defense, Growth, and Their Trade-Offs<p> Molecular Science 23 (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35409303&query_hl=3&itool=pubmed_docsum">35409303</a></dd></dl></div>]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Suppressor of silencing 2b, Cucumber mosaic virus (CMV): <a href="http://www.uniprot.org/uniprot/Q66125">Q66125</a><br></dd><dd>Protein TIFY 10A/JAZ1, <em>Arabidopsis thaliana </em> (Mouse-ear cress): <a href="http://www.uniprot.org/uniprot/Q9LMA8">Q9LMA8</a><br></dd>]]> </content></entry> <entry> <title>rupture</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-265.html" /> <id>tag:web.expasy.org,2024:/spotlight//2.929</id> <published>2024-01-19T15:50:18Z</published> <updated>2024-01-19T16:10:30Z</updated> <summary>Who has not been accosted by someone they would prefer to avoid? You greet them meekly, exchange a few polite words while wondering how to cut the exchange short without being disrespectful. If being disrespectful is not an issue, however, things become gloriously easy. You could tell them that their company bores you, that you have more important things to tend to or interrupt the chat with a brisk shake of the hand and move on. If you were part of a cartoon strip, you could burst into flames or simply disintegrate. It so happens that cells can actually opt to disintegrate when dealing with something that has become toxic to their environment, or at any rate redundant. This can be a virus, a bacterium, or perhaps simply age. Such an option is generally called programmed cell death, or apoptosis. And as there are many ways of being disrespectful to your acquaintance, there are many ways a cell can choose to disappear. One is by generating fatal rips in its own plasma membrane. Though rips such as these have been observed by scientists for many years, plasma membrane rupture was long believed to be a passive event. Until a protein known as ninjurin-1 was discovered.</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>Who has not been accosted by someone they would prefer to avoid? You greet them meekly, exchange a few polite words while wondering how to cut the exchange short without being disrespectful. If being disrespectful is not an issue, however, things become gloriously easy. You could tell them that their company bores you, that you have more important things to tend to or interrupt the chat with a brisk shake of the hand and move on. If you were part of a cartoon strip, you could burst into flames or simply disintegrate. It so happens that cells can actually opt to disintegrate when dealing with something that has become toxic to their environment, or at any rate redundant. This can be a virus, a bacterium, or perhaps simply age. Such an option is generally called programmed cell death, or apoptosis. And as there are many ways of being disrespectful to your acquaintance, there are many ways a cell can choose to disappear. One is by generating fatal rips in its own plasma membrane. Though rips such as these have been observed by scientists for many years, plasma membrane rupture was long believed to be a passive event. Until a protein known as ninjurin-1 was discovered.</p></b> <div class="quoteleft">« The term 'programmed cell death' only appeared in the early 1960s. From a purely philosophical point of view, the notion that a cell could choose to die - albeit under given circumstances - seemed almost unethical. However, the 1970s and the advent of molecular biology changed such views which, all of a sudden, became attractive: a cell could plan its own demise. »</div> <p>Though a subtle difference between programmed cell death (PCD) and apoptosis is under debate, today, both words are usually used to describe the same thing by the great majority of biologists. That is to say, the intrinsic 'choice' a cell makes to end its own life. This is opposed to 'necrosis', the term used when a cell dies due to external factors, such as a cardiac arrest or poisoning. The word 'apoptosis' has Greek roots and literally relates to the periodic shedding of leaves in autumn. Hippocrates used it to describe gangrene, perhaps because he saw it as a kind of shedding of the skin. Almost two thousand years later, during the 18th and the 19th centuries, scientists began to take an interest in cell death which, in those days, was referred to as 'natural cell death'. <p>Until the early 20th century, the causes of natural cell death were attributed to mechanical changes, such as the swelling and subsequent bursting of a cell. However, the Scottish microbiologist Alexander Fleming (1881-1955) suggested that cell death could also be caused by chemical changes, such as the disintegration of the cell's chromatin which he had observed under the microscope. The term 'programmed cell death' only appeared in the early 1960s. From a purely philosophical point of view, the notion that a cell could choose to die - albeit under given circumstances - seemed almost unethical. However, the 1970s and the advent of molecular biology changed such views which, all of a sudden, became attractive: a cell could plan its own demise. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt265.jpg" alt="Timon Maxey"/><figcaption>Manawatu Gorge</figcaption><figcaption>by<a href="https://www.maxey.co.nz/"> Timon Maxey </a></figcaption><figcaption>instagram:<a href="https://www.instagram.com/timonmaxey/"> @timonmaxey</a></figcaption><dd><br></dd><figcaption>courtesy of the artist</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Rips, or tears, on a cell's plasma membrane had been observed for centuries and scientists thought they were passive, purely due to mechanical forces - following the swelling of a cell for instance, much like stretch marks that appear on skin when weight has been put on abruptly. However, it turns out that rips, or plasma membrane ruptures, are quite intentional. This became obvious when researchers discovered the protein ninjurin-1. »</div> <p>A cell can choose to put an end to its life in several ways. Frequently, more than one strategy is used: two strategies can occur in unison for instance, or one can trigger off a second. Sometimes, too, a cell can decide to delay its death to arrange a few things beforehand - this has been described in a previous article*. Which strategies does a cell choose? It can form pores in its plasma membrane, for example, fragment its DNA, or slow down its mitochondria. Each of these strategies is fatal, by letting vital constituents leave the cell, inhibiting novel protein synthesis or failing to provide ATP, respectively. If performed simultaneously, little hope is left for the cell. The upside? No harm is caused to neighbouring cells - as opposed to necrosis. <p>Rips, or tears, on a cell's plasma membrane had been observed for centuries and scientists thought they were passive, purely due to mechanical forces - following the swelling of a cell for instance, much like stretch marks that appear on skin when weight has been put on abruptly. However, it turns out that rips, or plasma membrane ruptures, are quite intentional. This became obvious when researchers discovered the protein ninjurin-1. Ninjurin-1 is widely expressed, especially in tissues of epithelial origin, where it seems to be involved in cell adhesion. Structurally, ninjurin-1 looks like a hairpin. The curved bend is formed by a pair of alpha-helices, as in a classic transmembrane protein embedded in the cellular membrane. The N- and C-terminal extremities jut out to bathe in the extracellular medium, and the N terminus carries 2 alpha-helices (alpha1 and alpha2) separated by a kink. <p>Scattered across a cell's plasma membrane, monomeric ninjurin-1 is inactive. But during PCD, researchers noticed that ninjurin-1 monomers polymerise to form filaments of varied length. Structurally, each filament is built in the style of a classical wooden fence. The transmembrane region remains embedded in the cellular membrane while the N-terminus plunges into it. Alpha2 positions itself parallel to the sides of the hairpin while, thanks to the kink, alpha1 juts out at 90 degrees, reaching out to bind to a neighbouring monomer. The height of each filament, or 'ninjurin-fence', thus spans the width of the cellular membrane. In this way, filaments form linear tears in the membrane, or their ends meet to form pore-like structures. Either way, vital cytosolic constituents are free to spill out into the extracellular medium. <p>PCD was observed in multicellular organisms to begin with. In fact, for a long time, it was thought that the notion of PCD could only apply to multicellular organisms, or at least to cells where some kind of cooperation, or sort of cellular society, exists. But towards the end of the 20th century, it became apparent that PCD also applied to unicellular organisms. In fact, researchers now believe that PCD actually originated in unicellular organisms - although, admittedly, the existing theories do point, one way or another, towards multicellular cooperation. As an example, in a colony of bacteria, an infected cell could decide to give up its life to put a halt to viral replication and, hence, the further spread of infection. <p>How is ninjurin-1 activated? Is it the target of another factor triggered off by PCD? Does it react to a molecular change in the plasma membrane? Or to a conformational change such as membrane swelling? Ninjurin-1 may respond to both kinds of cue - chemical and mechanical. So far, no one knows. Some helices, such as those found in ninjurin-1, are known to sense lipid-packing defects or inflections of the membrane, both of which could be the result of cell swelling. Despite its seemingly tragic outcome, PCD is an elegant biophysical mechanism used by cells to create fatal tears in their own membrane without causing damage to their neighbours. In fact, frequently, it is precisely to preserve them from harm. A mechanism such as this could open opportunities for healing cancers, infection and inflammatory diseases by forcing cells that have become harmful to their environment to commit suicide. <p>*<em>Protein Spotlight issue 252: </em> <a href="https://www.proteinspotlight.org/back_issues/252/"> <em>DELAYED</em> </a></figcaption> <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Durand P.M., Ramsey G.<p> The concepts and origins of cell mortality<p> History and Philosophy of the Life Sciences 46 (2023)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=37289372&query_hl=3&itool=pubmed_docsum">37289372</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>sound and silence</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-264.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.928</id> <published>2023-12-22T15:10:02Z</published> <updated>2023-12-22T15:36:34Z</updated> <summary>Like smells and tastes, sounds can whizz you back to forgotten places. The shriek of a seagull. The wash of waves. The crack of lightning. A motor's rumble. A Christmas carol. A childhood tune. More often than not, these castaway memories emerge wrapped in a delicate veil of magic. It is a wonderful feeling, of something you would like to know again but cannot, although it is there hidden deep inside you. A feeling we would be unable to remember were it not for our ears. Sound is sensed by way of vibrations that hit parts of our inner ear, an intricate part of mammalian anatomy. Here, vibrations are amplified, causing messages to be relayed to our brain that translates them into noise - which is what the act of hearing is. All sorts of proteins are involved in the perception of sound* but also in its unfortunate contrary: hearing impairment. One particular protein, connexin 26, forms intercellular channels in the cochlea of the inner ear so that molecules can transit from one cell to another. Connexin26 also happens to be involved in many forms of hearing impairment because, when dysfunctional, molecules are no longer able to pass. </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>Like smells and tastes, sounds can whizz you back to forgotten places. The shriek of a seagull. The wash of waves. The crack of lightning. A motor's rumble. A Christmas carol. A childhood tune. More often than not, these castaway memories emerge wrapped in a delicate veil of magic. It is a wonderful feeling, of something you would like to know again but cannot, although it is there hidden deep inside you. A feeling we would be unable to remember were it not for our ears. Sound is sensed by way of vibrations that hit parts of our inner ear, an intricate part of mammalian anatomy. Here, vibrations are amplified, causing messages to be relayed to our brain that translates them into noise - which is what the act of hearing is. All sorts of proteins are involved in the perception of sound* but also in its unfortunate contrary: hearing impairment. One particular protein, connexin 26, forms intercellular channels in the cochlea of the inner ear so that molecules can transit from one cell to another. Connexin26 also happens to be involved in many forms of hearing impairment because, when dysfunctional, molecules are no longer able to pass.</p></b> <div class="quoteleft">« Gap junctions are a means for cells to communicate with one another, while keeping things levelled and regulated, a little like orchestrating a roundtable without letting anything trouble the theme under discussion. As can be expected, gap junctions are expressed in a wide variety of cells, such as neural cells where they support neural differentiation and proliferation, cardiac cells where they dictate contraction, in the lens where mutations can bring about cataracts and in the inner ear to help us hear. »</div> <p>Connexin 26, or Cx26, is one of several proteins that form channels which gather at specific locations - called gap junctions - on cell membranes. Each channel spans the plasma membrane of one cell, crosses a thin extracellular region before plunging into the plasma membrane of a neighbouring cell - thus allowing the passage of molecules from one cell to another. Gap junctions are a means for cells to communicate with one another, while keeping things levelled and regulated, a little like orchestrating a roundtable without letting anything trouble the theme under discussion. As can be expected, gap junctions are expressed in a wide variety of cells, such as neural cells where they support neural differentiation and proliferation, cardiac cells where they dictate contraction, in the lens where mutations can bring about cataracts and in the inner ear to help us hear. In this respect, several mutations in Cx26 are responsible for certain forms of hearing impairment (HI) - an ailment which affects 1 to 3 children out of 1000 at birth or during early childhood. <p>Gap junctions are dynamic structures, with channels being replaced and recycled on a regular basis. The channels themselves are formed in several steps. To begin with, half-channels are produced within each cell and whipped off to the plasma membrane along microtubular tracks, probably as part of a secretory pathway. In this way, one cell produces one half of a future channel, while the next one over produces the second half. Once in the plasma membrane, each half-channel then travels to a docking region in a gap junction, probably with the help of cytoskeletal actin. Once the two halves have reached their destination, they join in the extracellular region. Thus docked and locked, the two former half-channels now form an entire intercellular channel permeable to specific molecules. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt264.jpg" alt="Nana Shiomi"/><figcaption>One Hundred Views of Mitate No.67 Drum</figcaption><figcaption>woodcut print, 2004</figcaption><figcaption>by<a href="https://www.nanashiomi.com/"> Nana Shiomi </a></figcaption><dd><br></dd><figcaption>courtesy of the artist</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Cx26 has been extensively studied because of its role in sound transduction and hearing impairment. The overall ribbon representation of Cx26 looks like a wonderful firework of party streamers that is reflected on water. More prosaically, channels such as these have been compared to the Japanese hand drum, the tsuzumi, which is narrow in its centre while both ends widen out. »</div> <p>Several proteins form gap junction channels in the mammalian inner ear, which is made up of three main parts: the cochlea, the labyrinth and the vestibule, all three bathed in various fluids. The cochlea is what we use for hearing, while the vestibule and the labyrinth support our sense of balance. Cx26 is widely expressed in the cochlea, where it is involved in the maintenance of ionic and metabolic homeostasis as well as in intercellular signalling. Potassium ions, K+, are known to be at the heart of sensory transduction. Cx26 could be involved in maintaining cochlear homeostasis by sustaining the dynamics - removal and recycling - of K+ within the organ. However, there is a great chance that Cx26 is involved in the flux of other molecules too, such as Ca2+ ions and inositol phosphates. <p>The half-channels discussed above are also known as connexons. Each connexon is a hexamer of monomers, or connexins. A fully-fledged gap junction channel is therefore a dodecamer, i.e. the union of two connexons. There are 21 different connexins (one of which is Cx26) in the human proteome, which combine to form homo- or heteromeric connexons. Connexons will then go on to form homo- or heterotypic channels. It is not hard to understand that such combinations create an astounding diversity of gap junction channel composition and function. <p>Cx26, in particular, has been extensively studied because of its role in sound transduction and hearing impairment. Each connexin has three distinctive structural elements essential for the channel's overall function: four transmembrane alpha helices, an N-terminal helix which protrudes into the lumen of the channel, and two extracellular loops that are essential for connexon docking. Imagine six sets of four alpha helices, i.e. a connexon, that joins to another six sets of four alpha helices to form a full channel. The overall ribbon representation looks like a wonderful firework of party streamers that is reflected on water. More prosaically, channels such as these have been compared to the Japanese hand drum, the tsuzumi, which is narrow in its centre while both ends widen out. <p>How do molecules travel from one cell to another? Are the channels always open? Or do they close? An elegant 'plug gating' model has been proposed. Each connexin's N-terminal helix (NTH) protrudes into the channel's lumen. When there is no difference between the cells' membrane voltages, the NTHs are held against the inside of the channel thus leaving room for molecules to pass, similar to you pressing against a wall to let something wide pass. When there is a difference in membrane voltage between the two cells, the NTHs are released from the sides and join in the channel's centre to form a plug, through which nothing can pass. <p>It is a wonderfully refined model. What is more, it seems that Cx26 frequently combines with another connexin (connexin 30), which could explain why waves of Ca2+ spread far faster through cells with a combined channel as opposed to one composed only of Cx26. It is easy to understand that if Cx26 is dysfunctional, the transduction of sound will be affected. So far, about 90 mutations have been characterised in the Cx26 gene, several of which directly influence hearing either because connexons are malformed, or because they are mistargeted or fail to dock for example. Today, roughly 6% of the world's population suffers from HI due to genetic and environmental factors. It is an affliction which spreads silently across the world. Understanding the nooks and crannies of our cochlea may help to bring sound back to those who have lost it. <p>*<em>Protein Spotlight issue 22: </em> <a href="https://www.proteinspotlight.org/back_issues/022/"> <em>Pump Up The Volume</em> </a></figcaption> <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Defourny J., Thiry M.<p> Recent insights into gap junction biogenesis in the cochlea<p> Developmental Dynamics 252:239-246(2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=36106826&query_hl=3&itool=pubmed_docsum">36106826</a></dd><dd>2. Maeda S., Tsukihara T.<p> Structure of the gap junction channel and its implications for its biological functions<p> Cell. Mol. Life Sci. 68:1115-1129(2011)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=20960023&query_hl=3&itool=pubmed_docsum">20960023</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Gap junction beta-2 protein, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/P29033">P29033</a><br></dd>]]> </content></entry> <entry> <title>hot</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-263.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.927</id> <published>2023-11-24T11:28:16Z</published> <updated>2023-11-24T11:52:33Z</updated> <summary>The further south and east you go, the spicier food tends to get. A spice many of us store in the kitchen cupboard are chili peppers. Fresh or dried, crushed or finely sliced and thrown into a sauce, chili peppers can set your palate on fire to varying degrees. It has to do with the amount you fling in, but also the kind of pepper you choose to chop. The substance that sparks off the well-known mixture of burn and sometimes pain is known as capsaicin - and the sensation of pain is exactly what we are supposed to feel. Chili peppers do not produce capsaicin for human pleasure and cuisine; they make it to ward off predators. No other mammal would dream of adding hot pepper to its meal! Not all peppers are pungent, however. Take bell peppers, for example. Do they produce capsaicin? No. Instead, they produce what is known as capsiate, which is not hot. Both capsaicin and capsiate are derived from the same pathways but, at the very last steps, a vanillin substrate is modified in either one of two ways. The resulting product is capsiate or capsaicin - both of which, surprisingly, are synthesized by the same enzyme, a synthase known as PUN1. </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 further south and east you go, the spicier food tends to get. A spice many of us store in the kitchen cupboard are chili peppers. Fresh or dried, crushed or finely sliced and thrown into a sauce, chili peppers can set your palate on fire to varying degrees. It has to do with the amount you fling in, but also the kind of pepper you choose to chop. The substance that sparks off the well-known mixture of burn and sometimes pain is known as capsaicin - and the sensation of pain is exactly what we are supposed to feel. Chili peppers do not produce capsaicin for human pleasure and cuisine; they make it to ward off predators. No other mammal would dream of adding hot pepper to its meal! Not all peppers are pungent, however. Take bell peppers, for example. Do they produce capsaicin? No. Instead, they produce what is known as capsiate, which is not hot. Both capsaicin and capsiate are derived from the same pathways but, at the very last steps, a vanillin substrate is modified in either one of two ways. The resulting product is capsiate or capsaicin - both of which, surprisingly, are synthesized by the same enzyme, a synthase known as PUN1.</p></b> <div class="quoteleft">« Why are peppers sometimes pungent? Pungency keeps predators away. When you slice a fresh chili pepper in two, you will notice a line of whitish seeds that are attached to a pithy formation in the fruit's centre. It is in this pithy formation that capsaicin is synthesized. When an animal crunches a hot pepper, capsaicin is released and heads straight for the animal's nociceptors, triggering off the sensation of pain. This is exactly what happens in our mouths, and on our skin for that matter. »</div> <p>Pungent chili peppers and their non-pungent counterpart, bell peppers also known as paprikas, belong to the plant genus <em>Capsicum</em>. These peppers first grew in Central America, possibly in the region of today's Bolivia, and are believed to be one of the earliest domesticated plants, with archaeological evidence dating back 7000 years. Like many other much-appreciated South American plants, Christopher Columbus brought several pungent peppers back to Spain, from where they made their way across Europe to the rest of the world. Over the centuries, human fondness for the kick chili pepper gives to food has never ceased to grow, so much so that it has become one of the planet's major spice crops, with about 40 million tons of chili pepper fruits produced globally and on a yearly basis - although part of this production is used for medicinal and industrial purposes. <p>Why are peppers sometimes pungent? Pungency keeps predators away - especially mammals that like fruit. When you slice a fresh chili pepper in two, you will notice a line of small whitish seeds that are attached to a pithy formation in the fruit's centre, full of placental cells. It is in this pithy formation that capsaicin - like capsiate for that matter - is synthesized. When an animal crunches a hot pepper, capsaicin is released and heads straight for the animal's nociceptors, triggering off the sensation of pain. This is exactly what happens in our mouths, and on our skin for that matter. Once burnt by a chili pepper, there is a fair chance that a frugivorous mammal will not try to eat one again. Pungency is the plant's very effective way of protecting its seeds, and therefore its progeny. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt263.jpg" alt="Eric Ravilious"/><figcaption>KETTLE AND FLAMES</figcaption><dd><br></dd> <figcaption>by Eric Ravilious (1903-1942)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Pungency is caused by capsaicin, itself located in the pithy part of the inside of fresh chili pepper fruits. The compound was isolated in the early 1900s. Its chemical composition was determined at the turn of the 20th century, yet it took many more years to pin down the biosynthetic pathways leading to it. Today we know that capsaicin is synthesized by way of two independent biosynthetic pathways: one which begins with the amino acid phenylalanine, and the other with valine. »</div> <p>Surprisingly, birds can eat hot peppers without suffering from any kind of pain. This is because birds do not have nociceptors for capsaicin. What is more, the seeds pass straight through a bird's digestive tract untouched so the pepper's seeds are still able to germinate once ejected - whereas with mammals, the seeds are ground between molars or broken-down during digestion, thus losing all capacity for germination. Why would birds be insensitive to capsaicin? Birds are wonderful dispersers of plant seeds, such as chili pepper seeds of course. In fact, birds have hugely expanded the current habitat of <em>Capsicum</em> while also contributing to its genetic diversity. So, it could only have been a good move for Nature to select birds that are oblivious to chili pepper pungency while keeping the seeds intact as they pass through the avian digestive tract. <p>Pungency is thus caused by capsaicin, itself located in the pithy part of the inside of fresh chili pepper fruits. The compound was isolated in the early 1900s. Its chemical composition was determined at the turn of the 20th century, yet it took many more years to pin down the biosynthetic pathways leading to it. Today we know that capsaicin is synthesized by way of two independent biosynthetic pathways: one which begins with the amino acid phenylalanine, and the other with valine. A series of events turns phenylalanine into vanillylamine on the one hand, and valine into the branched fatty acid 8-methyl-6-nonenoyl-CoA on the other. Vanillylamine and 8-methyl-6-nonenoyl-CoA are then condensed by a capsaicin synthase that catalyses an amide bond formation to produce capsaicin: 8-methyl-N-vanillyl-6-nonenamide. Capsaicin synthase, or PUN1, does the job on its own, as a monomer, with no additional help from cofactors or associated proteins. <p>What about peppers like paprika? Does their lack of spice have anything to do with PUN1? Surprisingly: yes. Remember, capsaicin is produced by the condensation of vanillylamine and 8-methyl-6-nonenoyl-CoA. Just one step upstream, vanillin is converted to vanillylamine by an aminotransferase called pAMT. However, it turns out that vanillin can also be reduced to vanillyl alcohol by an alcohol dehydrogenase known as CAD1, or cinnamyl alcohol dehydrogenase. In the absence of vanillylamine, PUN1 simply turns to vanillyl alcohol to which it adds the same fatty acid 8-methyl-6-nonenoyl-CoA thus catalysing the formation of the non-pungent capsiate. So pungency depends on whether vanillin is converted to vanillyl alcohol or to vanillylamine. But what decides on whether a pepper will be hot or not? CAD1 happens to be involved in lignin synthesis, and has therefore been around for a long time in peppers, as it has in all plants. pAMT was probably acquired later in time, selected by certain varieties of <em>Capsicum</em> as a means to fight off predators with capsaicin. It remains to be proved, but pAMT can be seen as something that is optional in peppers. The spice of a pepper would then depend on the level of pAMT expression. <p>There is a chance that evolution coaxed non-pungent peppers to become pungent peppers. Certainly, ever since capsaicin was discovered, it has not only been widely used as a spice but also as an analgesic to... relieve pain. It is used to treat human disorders such as obesity, diabetes, cancer and cardiovascular diseases, although evidence that it actually does help remains scant. Capsaicin is equally used to fight off pests such as voles, squirrels, insects and dogs, and in the form of pepper spray in riot controls or even, in some countries, it is carried in the bottom of bags to be pulled out when needed as a means of self-defence. Certainly, since Columbus and his travels, capsaicin has become an undeniable part of our lives. It is unexpected, too, that humans have chosen to season their food with something that has been modelled to cause pain. Although recent findings do suggest that capsaicin triggers off positive effects in the human brain. An explanation perhaps. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Stewart Jr. C., Kang B.-C., Liu K. et al.<p> The Pun1 gene for pungency in pepper encodes a putative acyltransferase<p> The Plant Journal 42:675-688(2005)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15918882&query_hl=3&itool=pubmed_docsum">15918882</a></dd><dd>2. Sano K., Uzawa Y., Kaneshima I. et al.<p> Vanillin reduction in the biosynthetic pathway of capsiate, a non-pungent component of Capsicum fruits, is catalyzed by cinnamyl alcohol<p> Nature Scientific Reports 12:12384 (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35858994&query_hl=3&itool=pubmed_docsum">35858994</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Acyltransferase Pun1, <em>Capsicum annuum</em> (Capsicum pepper): <a href="http://www.uniprot.org/uniprot/D2Y3X2">D2Y3X2</a><br></dd><dd>Cinnamyl alcohol dehydrogenase 1, <em>Capsicum annuum</em> (Capsicum pepper): <a href="http://www.uniprot.org/uniprot/B5LAT8">B5LAT8</a><br></dd><dd>Vanillin aminotransferase, <em>Capsicum annuum</em> (Capsicum pepper): <a href="http://www.uniprot.org/uniprot/E1AQY3">E1AQY3</a><br></dd>]]> </content></entry> <entry> <title>self-reliant</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-262.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.926</id> <published>2023-10-19T11:22:53Z</published> <updated>2023-10-19T11:50:44Z</updated> <summary>In times of perplexity, every now and then it is better to deal with things yourself. It can be a time-saver, and sometimes, too, an energy-saver. If faced, say, by an oncoming downpour, it is wiser to run for shelter rather than wait for someone to bring you an umbrella. Such decisions also exist at the cellular level. Take our immune system for instance. When attacked by a virus, our body begins by rapidly firing off a first round of artillery as it awaits further and more complex lines of defence that involve myriads of other factors. It turns out that the use of fast lanes such as these also occur at a far smaller scale. In this light, scientists recently discovered quite an extraordinary protein, known as ophMA, that belongs to the fungus Omphalotus orealius, which methylates its own C-terminal tail instead of depending on another transferase to do the job. The tail is then cleaved and folds into a cyclic peptide, an omphalotin, that has anti-nematode properties. Besides its talent for independence, ophMA also adopts a rare catenane arrangement, very similar to two rings that have been interlocked.</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>In times of perplexity, every now and then it is better to deal with things yourself. It can be a time-saver, and sometimes, too, an energy-saver. If faced, say, by an oncoming downpour, it is wiser to run for shelter rather than wait for someone to bring you an umbrella. Such decisions also exist at the cellular level. Take our immune system for instance. When attacked by a virus, our body begins by rapidly firing off a first round of artillery as it awaits further and more complex lines of defence that involve myriads of other factors. It turns out that the use of fast lanes such as these also occur at a far smaller scale. In this light, scientists recently discovered quite an extraordinary protein, known as ophMA, that belongs to the fungus <em>Omphalotus orealius</em>, which methylates its own C-terminal tail instead of depending on another transferase to do the job. The tail is then cleaved and folds into a cyclic peptide, an omphalotin, that has anti-nematode properties. Besides its talent for independence, ophMA also adopts a rare catenane arrangement, very similar to two rings that have been interlocked.</p></b> <div class="quoteleft">« Omphatolins are cyclic highly-methylated peptides and have been known, since the turn of the 21st century, to specifically target the nematode <em>Meloidogyne incognita</em>, a common plant pathogen. Since the peptide's structure resembles that of another renowned fungal cyclic peptide, cyclosporine, scientists assumed that omphatolins were synthesized in the same way. Until, much to everyone's surprise, its sequence was spotted on Omphalotus olearius' genome. This could imply that the peptide is synthesized by a ribosome - something no one had expected, let alone considered. »</div> <p>Omphatolins are produced by Omphalotus olearius - a mushroom also known as Jack O'Lantern, because of its deep orange colour akin to that of pumpkins and its soft green bioluminescent glow at night. Omphatolins are cyclic highly-methylated peptides and have been known, since the turn of the 21st century, to specifically target the nematode <em>Meloidogyne incognita</em>, a common plant pathogen. Since the peptide's structure resembles that of another renowned fungal cyclic peptide, cyclosporine, scientists assumed that omphatolins were synthesized in the same way. That is to say, their synthesis does not rely on the help of ribosomes but rather on huge multi-modular enzymes called non-ribosomal peptide synthetases (NRPs). Such enzymes are able to build peptide sequences - i.e. to create amide bonds - without resorting to the ribosome's complex machinery. <p>No one, however, was able to pin down what was making omphalotin. Until, much to everyone's surprise, its sequence was spotted on Omphalotus olearius' genome. This could imply that omphalotin is synthesized by a ribosome - something no one had expected, let alone considered, given its similarity to cyclosporine. As their name implies, RiPPs (for Ribosomally synthesized and Posttranslationally modified Peptides) are synthesized via the regal ribosomal machinery with its tango of mRNA, rRNA, amide bonding, post-translational modifications and proteolytic cleavage. This turned out to be partly true for omphalotin: it is a RiPP, but of a different kind. Omphalotin actually forms the C-terminal end of a far longer sequence whose N-terminal end is a methyltransferase - the very methyltransferase that methylates omphalotin! Since this discovery, many other peptides of the same nature continue to surface and are now collectively known as borosins, i.e. macrocyclic peptides whose leader sequence (gross modo the methyltransferase) is very long. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt262.jpg" alt="Henri Gaudier Brzeska "/><figcaption>THE WRESTLERS</figcaption><dd><br></dd> <figcaption>by Henri Gaudier Brzeska (1891-1915)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« OphMA acts as a homodimer where each monomer locks into the other to adopt a catenane arrangement - a very rare arrangement of two enzymes - most probably providing stability to ophMA. »</div> <p>OphMA designates both the methyltransferase (M) and omphalotin (A). About 400 amino acids long, ophMA is divided, roughly, into three main domains: a large N-terminal methyltransferase domain, followed by what has been called a clasp domain and then a C-terminal core peptide that will give rise to the cyclic peptide omphalotin - itself barely twelve amino acids long. When omphalotin is required, the methyltransferase methylates nine out of twelve of the peptide's amide bonds. Methylation is believed to occur, amide bond by amide bond and in the same direction, either as the peptide is being cyclised or once it has been cyclised. <p>The process sounds straightforward but is actually quite complex as it involves a very rare chemical arrangement known as a catenane. A catenane is a molecular architecture where two - or more - macrocycles are interlocked in the manner of intertwined rings. Remember the Christmas decorations you made at school? Where you took a strip of coloured paper that you glued at the ends to form a circle? Then you took a second strip, inserted one end through the paper circle you had just made, and glued its ends? That is a two-ringed catenane - which can only be disrupted if the covalent bonds holding one ring are broken, or if you tear one of the strips of coloured paper. <p>OphMA acts as a homodimer where each monomer locks into the other - just like our Christmas decorations - to adopt a catenane arrangement. How does it happen? First, the methyltransferase and the clasp domains of one monomer move towards each other to form a ring-like structure. The clasp domain of one monomer then wraps around the methyltransferase domain of the other, and the core domain (i.e. the future omphalotin) of one monomer inserts itself into the active site of the other monomer. The result is a very rare catenane arrangement of two enzymes - most probably providing stability to ophMA. <p>The active site becomes an extended hydrophobic tunnel in which sits the peptide substrate, ready to be methylated. Conformational changes abound as methylation occurs - with the help of a cofactor, S-adenosyl methionine or SAM - on the amide bonds, one transfer after another, as the substrate performs 180 degree flips to bring the next residue into the active site. Consequently, each methyltransferase in the ophMA dimer methylates the substrate peptide that belongs to its monomer as opposed to its own. <p>It is a wonderful strategy. A sort of "you scratch my back, I'll scratch yours". What is more, with the methyltransferase at the substrate's immediate disposal, there is no need to find an external transferase, so to speak, which would only involve additional energy- and time-consuming biological processes. The methylated peptide is cleaved by another enzyme (called ophP) and cyclised to yield the finished cyclic peptide with nine methylated amide bonds conferring both stability and cell permeability. At this point, one would imagine that the catenane arrangement has collapsed - or is on the point of collapsing - as the methyltransferase is discarded and omphalotin is sent to its target. <p>Despite knowing in great detail how omphalotin is made, how it is toxic to <em>Meloidogyne incognita</em> is still not understood. Perhaps, like cyclosporine, it is able to glide easily through the cell membranes and block important enzymes in the cytoplasm. Although no one yet knows which enzymes are blocked... What is particularly interesting for researchers is that omphalotin is only specific to Meloidogyne incognita, a known and wide-spread plant pathogen, yet it is not toxic to bacteria or other fungi. So, as a pesticide against a given crop, it should do little harm to the environment. What is more, ophMA does not seem to be very watchful and joyfully methylates residues that have been artificially replaced by others - which could help scientists suggest fine-tuned versions of the peptide for a given therapeutical or agricultural use. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Ramm S., Krawczyk B., Mülenweg A., et al.<p> A self-sacrificing N-methyltransferase is the precursor of the fungal natural product omphalotin<p> Angew. Chem. Int. Ed. 56:9994-9997(2017)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=28715095&query_hl=3&itool=pubmed_docsum">28715095</a></dd><dd>2. Song H., Naismith J.H.<p> Enzymatic methylation of the amide bond<p> Current Opinion in Structural Biology 65:79-88(2020)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=32653730&query_hl=3&itool=pubmed_docsum">32653730</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Methyltransferase/ribosomally synthesized cyclic peptide omphalotin A precursor ophMA, <em>Omphalotus olearius</em> (Jack O'Lantern): <a href="http://www.uniprot.org/uniprot/A0A2R2JFI5">A0A2R2JFI5</a><br></dd>]]> </content></entry> <entry> <title>in good time</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-261.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.925</id> <published>2023-09-18T08:51:28Z</published> <updated>2023-09-28T10:14:47Z</updated> <summary>When my daughter was born, I could not help but realise that she already had inside her what would participate in giving life, if she so chose, to a daughter or a son of her own. Given a little thought, it is an extraordinary state of affairs. My daughter's ovaries were already filled to the brim with a life-time's stock of egg cells, albeit not quite mature. As it so happened, my next child was a baby boy, and I knew he would only begin to produce germ cells at puberty and cease to produce them when his life comes to an end. It is a fundamental difference between the two sexes, which obviously entails very distinct physiological makeups. Notably, on an average, egg cells must remain healthy during the best part of two decades, at the very least in these parts of the world, before one, or two, or perhaps several more are actually fertilised. Fertility is hugely dependent on egg-cell fitness, which is why many mechanisms exist to protect not only an egg's integrity but also elemental macromolecules and organelles whose activities are temporarily arrested. One protein known as ZAR1, from Zygote ARrest 1, is at the heart of such a mechanism.</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 my daughter was born, I could not help but realise that she already had inside her what would participate in giving life, if she so chose, to a daughter or a son of her own. Given a little thought, it is an extraordinary state of affairs. My daughter's ovaries were already filled to the brim with a life-time's stock of egg cells, albeit not quite mature. As it so happened, my next child was a baby boy, and I knew he would only begin to produce germ cells at puberty and cease to produce them when his life comes to an end. It is a fundamental difference between the two sexes, which obviously entails very distinct physiological makeups. Notably, and at the very least in these parts of the world, egg cells must remain healthy during the best part of two decades before one, or two, or perhaps several more are actually fertilised. Fertility is hugely dependent on egg-cell fitness, which is why many mechanisms exist to protect not only an egg's integrity but also elemental macromolecules and organelles whose activities are temporarily arrested. One protein known as ZAR1, from Zygote ARrest 1, is at the heart of such a mechanism.</p></b> <div class="quoteleft">« Before puberty and ovulation, human egg cells are immature and the great majority of them will remain in this state until the onset of menopause. At puberty, however, a minority of these immature egg cells will be swept from the ovaries into the Fallopian tubes fully expecting to bump into a sperm cell. On this trip, the chosen egg cells mature into full-blown oocytes, ready to be fertilised. »</div> <p>For the sake of simplicity, let us talk about human germ cells only. Mature human egg cells, like sperm cells, carry inside them half of the genetic makeup of what may one day become a human being. At the very beginning, that is before puberty and the onset of ovulation, egg cells are immature and the great majority of them will remain in this state until the onset of menopause. At puberty, however, usually one by one and every month, a minority of these immature egg cells will be swept from the ovaries into the Fallopian tubes fully expecting to bump into a sperm cell. While on this trip, the chosen egg cells mature into full-blown oocytes, ready to be fertilised. <p>What is meant by egg-cell maturation? What are oocytes? To cut a long story short, egg cells go through two distinct types of division, called meiosis I and meiosis II. Meiosis I is the dividing mechanism by which germ cells swap bits of their DNA, thus creating novel DNA which will be unique to every germ cell. It is a source of genetic richness and how Nature, with the help of evolution, manages to produce such a variety of organisms, even within a given species. Meiosis II is the dividing mechanism that follows meiosis I to produce mature egg cells, or oocytes, each of which carries only one copy of the novel DNA. Immature egg cells are stuck between meiosis I and II until puberty, and only a selected few will fully mature upon ovulation. By bonding with a mature sperm cell, the fertilised egg - or zygote - recovers the requisite two copies of DNA. A zygote thus represents the very first cell we all begin as. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt261.jpg" alt="Andrea Bonnet"/><figcaption>by Andrea Bonnet, 2011</figcaption><dd><br></dd> <figcaption>part of a project with art students in 2011</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« What holds egg cells in their immature state? And what shifts them into maturity? Part of the answer is protein ZAR1. ZAR1 is responsible for generating a sort of jelly that traps mitochondria and dormant maternal mRNAs into gelatinous bubbles that are found throughout the egg cell's cytoplasm. Such a membraneless structure provides stability to translationally repressed maternal mRNAs - a minority of which are only triggered into action twenty, thirty perhaps even as much as forty or fifty years later. »</div> <p>Egg cell maturation is not only a question of DNA. Egg cells are full of other macromolecules and organelles, all of which are essential for their survival. Two examples are maternal mRNAs and mitochondria. Maternal mRNAs are mRNAs that belong to both the immature and the mature egg cell and are translated into required protein until the newly formed zygote can transcribe its own mRNAs. Maternal mRNAs are involved in essential roles such as translation and mitochondrial function. In a way, they constitute the yoke of germ cells. Maternal mRNAs are kept dormant in immature egg cells - as are mitochondria that have little need to produce energy for cells whose activity has been arrested. <p>What holds egg cells in their immature state? And what shifts them into maturity? Part of the answer is protein ZAR1. ZAR1 is responsible for generating a sort of jelly that traps mitochondria and dormant maternal mRNAs into gelatinous bubbles that are found throughout the egg cell's cytoplasm. Such a membraneless structure provides stability to translationally repressed maternal mRNAs - a minority of which are only triggered into action twenty, thirty perhaps even as much as forty or fifty years later. Besides giving rise to the gel, ZAR1 also acts as a ribonucleoprotein by binding to maternal mRNAs. This jelly-like bubble full of mitochondria and maternal mRNAs has been given the name Mitochondria-Associated Ribonucleprotein DOmain, or MARDO. ZAR1 is thus one of the major players in MARDO assembly. <p>ZAR1 sculpts MARDOs while also acting as a ribonucleoprotein (RBP). Indeed, ZAR1 has a conserved C terminus, a zinc-binding motif typically found in RBPs like transcriptional activators, repressors or cofactors. A disordered region, on the other hand, is found in ZAR1's N-terminal region. These recently discovered regions in protein sequences are known to adopt varied 3D conformations according to the environment - an observation which shattered the ongoing 'structure-function' paradigm that had prevailed up until the eve of this century*. In ZAR1, this disordered region forms the scaffold for MARDO assembly. When an egg cell matures, and if it is further fertilised, maternal mRNAs will continue to be translated until the zygote begins to transcribe its own - ZAR1 is then completely degraded, the MARDOs disrupted, and their mitochondria released to resume function. The remaining maternal RNAs, now redundant, are broken down. <p>Other RBPs are found in MARDOs as are other macromolecules, many of which are no doubt involved in building up and strengthening the protective gelatinous bubbles. But ZAR1 is central in their architecture since without it, MARDOs are unable to form. Many questions remain to be answered. Why, for instance, does the membrane potential of mitochondria increase during MARDO formation? Why are there numerous mitochondrial clusters distributed throughout the cells and not just one huge one? Understanding MARDOs in detail will no doubt help to grasp problems related to female infertility. It is not hard to see that if ZAR1 is dysfunctional one way or another, there is little chance that egg cells will mature. A humbling thought. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Cheng S., Altmeppen G., So C. et al. <p> Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment<p> Science 378 (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=36264786&query_hl=3&itool=pubmed_docsum">36264786</a></dd><dd>2. Wu Y.-K., Fan H.-Y.<p> Revisiting ZAR proteins: the understudied regulator of female fertility and beyond<p> Cell and Molecular Life Sciences 79 (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35072788&query_hl=3&itool=pubmed_docsum">35072788</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Zygote arrest protein 1, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q86SH2">Q86SH2</a><br></dd><dd>Zygote arrest protein 1, <em>Mus musculus</em> (Mouse): <a href="http://www.uniprot.org/uniprot/Q80SU3">Q80SU3</a><br></dd>]]> </content></entry> <entry> <title>clearing the clamour</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-260.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.924</id> <published>2023-07-26T08:03:41Z</published> <updated>2023-07-26T08:35:24Z</updated> <summary>There is an invisible and silent law that causes clutter to emerge and grow unless action is taken to deal with it. Who has not stood in the middle of a littered room and thought "Right, this needs clearing.". And for some reason, clearing clutter has this wonderful ability of also rinsing your mind. The same goes for cells. It begins at the molecular level and is called cell homeostasis, which is at the heart of any organism's health. Intracellular bodies (organelles) known as lysosomes have a major role in animal cell homeostasis, as they degrade components that are toxic to the cell, or foreign, or simply - like foodstuffs gone well beyond their sell-by dates - too old to be of any more use. When infected by bacteria, for instance, our body organises a swift initial response by calling up specialised cells known as macrophages whose role is to engulf and destroy invading pathogens. Macrophages perform this by way of their numerous lysosomes - but more importantly thanks to a protein known as TFEB that, upon infection, is activated to stimulate lysosome biosynthesis.</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 is an invisible and silent law that causes clutter to emerge and grow unless action is taken to deal with it. Who has not stood in the middle of a littered room and thought "Right, this needs clearing.". And for some reason, clearing clutter has this wonderful ability of also rinsing your mind. The same goes for cells. It begins at the molecular level and is called cell homeostasis, which is at the heart of any organism's health. Intracellular bodies (organelles) known as lysosomes have a major role in animal cell homeostasis, as they degrade components that are toxic to the cell, or foreign, or simply - like foodstuffs gone well beyond their sell-by dates - too old to be of any more use. When infected by bacteria, for instance, our body organises a swift initial response by calling up specialised cells known as macrophages whose role is to engulf and destroy invading pathogens. Macrophages perform this by way of their numerous lysosomes - but more importantly thanks to a protein known as TFEB that, upon infection, is activated to stimulate lysosome biosynthesis.</p></b> <div class="quoteleft">« For years, lysosomes were seen as a place where cells dump their waste to have it recycled. But, as time went by, things turned out to be far more nuanced than that. Lysosomes vary in size and morphology as well as in enzyme content, meaning that they are destined to deal with different substrates - a little like the different bins we use for recycling paper, aluminium or organic waste for example. »</div> <p>The immune response involves several of the most intricate metabolic pathways known to biologists. When a pathogen finds its way into our body, it begins by sparking off what can be described as a rather basic immune response: a first line of defence known as the innate immune response. This involves cells specifically equipped to get rid of material that is foreign to the body. Among these specialised cells are those known as macrophages. Macrophages are full of organelles, or lysosomes, themselves filled with enzymes whose prime function is to break down what comes in. <p>Lysosomes were discovered, quite by chance, in the very early 1950s by the Belgian cytologist and biochemist Christian de Duve. Famously, the scientist is known to have unveiled their existence not by examining cells under a microscope but by sheer inference as he and his group strove to understand the distribution of an enzyme, hexose phosphatase, in various cell fractions they were examining. One thing leading to another, it became clear that their enzyme was protected by "membrane sacs". These sacs marked the very beginnings of the "lysosome" concept, that is to say a membrane-bound organelle that contains acid hydrolases whose main role is to digest intracellular macromolecules. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt260.jpg" alt="Lyubov Popova"/><figcaption>Stage set design for 'The Magnanimous Cuckold' by Meyerhold</figcaption><dd><br></dd> <figcaption>by Lyubov Popova (1889-1924)</figcaption><dd><br></dd> </figure></div> <div class="quoteright">« Not so long ago, a surprising find was made. Itaconic acid, or itaconate, is widely used in the manufacture of polymers to make plastics and paint. One day, however, someone noticed that it had antibacterial properties. As researchers sought to understand the acid's biological activity, they discovered that large amounts were produced in macrophages. Could itaconate play a role in macrophage immune response? The answer is yes. »</div> <p>Accordingly, for years, lysosomes were seen as a place where cells dump their waste to have it recycled. But, as time went by, things turned out to be far more nuanced than that. Lysosomes are delimited by a membrane. They vary in size and morphology as well as in enzyme content, meaning that they are destined to deal with different substrates - a little like the different bins we use for recycling paper, aluminium or organic waste for example. What is digested is exported and recycled, which is why lysosomes were long regarded as mere cellular bins. We now know, however, that besides regulating cell homeostasis, lysosomes also play major roles in processes such as signal transduction, autophagy regulation, ageing, plasma membrane repair, animal development and... the immune response. <p>Not so long ago, a surprising find was made. Itaconic acid, or itaconate, is widely used in the manufacture of polymers to make plastics and paint. One day, however, someone noticed that it had antibacterial properties. Itaconate is produced by the Krebs cycle - the cycle that provides cells with energy. As researchers sought to understand the acid's biological activity, they discovered that large amounts were produced in macrophages. Could itaconate play a role in macrophage immune response? The answer is yes. It does this by modifying, via alkylation, a transcription factor known as TFEB whose role is to regulate the biosynthesis of lysosomes. In macrophages, notably. <p>Transcription factor EB (TFEB) is a member of the microphthalmia family of basic helix-loop-helix - leucine-zipper transcription factors, or simply MiT family, all of whom share an identical domain required for DNA-binding. The MiT family is particular in that its various members are able to bind to one another, forming either homodimers or heterodimers. In "dormant" macrophages, phosphorylated TFEB is sequestered in the cell cytoplasm by regulatory proteins. Upon bacterial infection, the production of itaconate in macrophages is rapidly increased, and the acid goes on to alkylate cytoplasmic TFEB. Alkylation interferes with the cytoplasmic phosphorylation of TFEB causing the regulatory proteins to lose their grip. TFEB is then free to migrate to the nucleus - a move elegantly explained by the possible unmasking of TFEB's nuclear localization signal (NLS), previously hidden by the regulatory proteins. In the nucleus, TFEB binds specifically to what are known as CLEAR (Coordinated Lysosomal Expression And Regulation) elements found on the promoter of lysosomal genes - thus prompting their activation and expression, and subsequent lysosomal biosynthesis. <p>To cut a long story short, TFEB orchestrates the transcription of a large array of genes whose products clear cells of undesirable material - a job so crucial to cell homeostasis and an organism's general health that evolution has made sure to conserve it. Several well-known diseases are caused by an over-accumulation of substrates in cells such as in Parkinson's, Huntington's or Alzheimer's disease, or even in lysosomes themselves - a disease known as lysosomal storage disorder (LSD). The overexpression of TFEB in murine models of these diseases has actually shown benefits, suggesting that TFEB could represent a common therapeutic strategy. But things are not so straightforward. Depending on its post-transcriptional modification and the level of cell stress, TFEB seems to be involved in several pathways other than cell homeostasis, such as ageing, DNA damage repair, or glucose and lipid metabolism. Far too many roles for TFEB to be taken lightly. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Napolitano G., Ballabio A.<p> TFEB at a glance<p> Journal of Cell Science 129:2475-2481(2016)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=27252382&query_hl=3&itool=pubmed_docsum">27252382</a></dd><dd>2. Zhang Z., Chen C., Yang F. <em>et al</em>.<p> Itaconate is a lysosomal inducer that promotes antibacterial innate immunity<p> Molecular Cell 82:2844-2857(2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35662396&query_hl=3&itool=pubmed_docsum">35662396</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>Transcription factor EB, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/P19484">P19484</a><br></dd>]]> </content></entry> <entry> <title>on ants, bandicoots and Gilbertian mimicry</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-259.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.923</id> <published>2023-06-29T10:03:25Z</published> <updated>2023-06-29T10:31:39Z</updated> <summary>Nature has its way of adapting to almost - if not every - known condition on Earth. It may take some time, but she gets there in the end. Adaptation has one sole aim: survival or, at the very least, a little more comfort. One of the most recent and dramatically rapid examples of biological adaptation occurred in Great Britain following the industrial revolution. Soot had begun to pollute cities which drove the peppered moth, Biston betalaria, to change its colour from speckled black to only black, making it far less conspicuous when resting against the soot-stained walls*. Many insects have devised ways to trick their predators through the art of mimicry. One ant, Myrmecia gulosa, commonly known as the giant bull ant makes use of a form of molecular mimicry: its body has not changed colour but the ant has acquired a protein that parodies a hormone which belongs to its predators, and is able to inflict lasting pain following a sting. The protein is known as OMEGA-myrmeciitoxin(02)-Mg1a, or simply Mg1a, and has recently been shown to mimic vertebrate epidermal growth factor. </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>Nature has its way of adapting to almost - if not every - known condition on Earth. It may take some time, but she gets there in the end. Adaptation has one sole aim: survival or, at the very least, a little more comfort. One of the most recent and dramatically rapid examples of biological adaptation occurred in Great Britain following the industrial revolution. Soot had begun to pollute cities which drove the peppered moth, <em>Biston betalaria</em>, to change its colour from speckled black to only black, making it far less conspicuous when resting against the soot-stained walls*. Many insects have devised ways to trick their predators through the art of mimicry. One ant, <em>Myrmecia gulosa</em>, commonly known as the giant bull ant makes use of a form of molecular mimicry: its body has not changed colour but the ant has acquired a protein that parodies a hormone which belongs to its predators, and is able to inflict lasting pain following a sting. The protein is known as OMEGA-myrmeciitoxin(02)-Mg1a, or simply Mg1a, and has recently been shown to mimic vertebrate epidermal growth factor.</p></b> <div class="quoteleft">« Myrmecia gulosa is a species of Myrmecia ant which produces a venom toxin of a particular nature. One of the first Australian insects to have been described by the larger than life British naturalist Sir Joseph Banks, all the way back in 1770, M.gulosa is abundant in the eastern part of Australia where it is known as the giant red bull ant or hoppy joe, as it is one of the Myrmecia ants that jumps when it feels at risk. »</div> <p><em>Myrmecia</em> ants are found almost exclusively in Australia and its coastal islands. Commonly known as bull ants (not to be confused with bullet ants) or bulldog ants, they are at least 75 million years old and considered to be the most primitive group of ants living on our planet. Long and slender, with two characteristic large mandibles, they can be aggressive and ferocious creatures, sometimes reaching the gruesome length of 40mm - not the kind of ant you want to meet at close quarters when you know that its sting is one of the nastiest in the ant world. <em>Myrmecia</em> ants are also known as jack jumpers because of the way several species are able to jump repeatedly - sometimes reaching a height of 10cm - when they feel threatened. Their sting, however, is also frequently used for catching prey, which can be many times larger than the ants themselves, like bees for example - and dessert comes in the form of honey dew or nectar. <p>Their vision, too, is unlike that of other ants. Particularly sharp, <em>Myrmecia</em> ants can perceive UV light, which means that they are able to see more colours than humans can. Their eyesight may even be more acute than a dog's or a cat's. Excellent vision is important since <em>Myrmecia</em> ants do not lay pheromone trails to find their way but actually rely on visual cues for navigation, and can distinguish forms that are situated one to two metres away. Some species do release pheromones, however, though not to find their way around but as a territorial alarm. Where do they live? Largely in the same places as the ants you come across in other parts of the world: forests, woodlands, grasslands, heath and even urban areas. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt259.jpg" alt="The Lobster Quadrille"/><figcaption>The Mock Turtle's Story - The Lobster Quadrille</figcaption><dd><br></dd> <figcaption>illustration by Arthur Rackham (1867-1939)</figcaption><dd><br></dd> </figure></div> <p>The sting of <em>Myrmecia</em> ants is one of the most toxic in the insect world. Back in the 1950s, scientists began to take a closer look at sting venom and discovered that it was made up of several components, or toxins, each of which caused a specific reaction in the ant's prey or predator - such as numbness or pain. This, however, was for bee and wasp venom; in those days, ant venom was believed to be simply formic acid. Then, in the 1960s, researchers discovered that bee, ant and wasp venom is composed of toxins, mostly of peptidic nature, i.e. peptides or proteins. Ever since, time and energy has been put into characterising them and defining their mode of action - because if we know how venom works then ways can be found to alleviate a painful sting. In some instances, even avoid death. <div class="quoteright">« Mg1a is very similar to the EGF-like peptide hormone sequences of marsupials - the Tammar wallaby, the koala bear, the common wombat, the fat-tailed dunnart and the long-nosed bandicoot - all of whom gladly make a meal out of M.gulosa. This is a startling example of adaptation where a creature mimics a model that belongs to its predator (here EGF) and promptly uses it to put its predator in danger - a form of mimicry that has been called Gilbertian mimicry. »</div> <p><em>Myrmecia gulosa</em> is a species of <em>Myrmecia</em> ant which produces a venom toxin of a particular nature. One of the first Australian insects to have been described by the larger than life British naturalist Sir Joseph Banks, all the way back in 1770, <em>M.gulosa</em> is abundant in the eastern part of Australia where it is known as the red bull ant or hoppy joe, as it is one of the <em>Myrmecia</em> ants that jumps when it feels at risk. The study of <em>M.gulosa</em> venom recently unveiled the existence of a peptide toxin which does not act in the same way as the other toxins and bears no structural resemblance to them either. Instead, this one had a secondary structure that seemed to echo, astonishingly, a mammalian epidermal growth factor, or EGF. Especially the EGFs of the wonderfully-named fat-tailed dunnart, long-nosed bandicoot and short-beaked echidna - to mention only three of these extraordinary Australian creatures who would not look out of place in Lewis Carroll's Lobster Quadrille. <p>Unlike other invertebrate and vertebrate EGF-like peptides, Mg1a has no propeptide, no transmembrane or cytoplasmic domain but simply a secretory signal peptide followed directly by the mature Mg1a - similar to most venom peptides. So, although its primary sequence is closer to that of a venom toxin, Mg1a adopts a secondary structure - namely an EGF-like fold - which mimics that of a mammalian EGF. In vertebrates, epidermal growth factors are mainly known to stimulate cell growth and differentiation and are active in instances such as wound healing. The process is triggered off when EGF binds to its receptor, itself lodged in the target cell's plasma membrane. Why would <em>M.gulosa</em> choose to produce a venom peptide that acts like EGF? Well, upon observation, it so happens that this EGF-like peptide hormone - called OMEGA-myrmeciitoxin(02)-Mg1a (Mg1a) - binds to the EGF receptors of the ants' mammalian predators thus inducing a long-lasting pain. A discovery which prompts the question: are mammalian EGFs involved in pain too? <p>Mg1a is very similar to the EGF-like peptide hormone sequences of marsupials - the Tammar wallaby, the koala bear, the common wombat, the fat-tailed dunnart and the long-nosed bandicoot - all of whom gladly make a meal out of <em>M.gulosa</em>. How does Mg1a cause pain? By specifically binding to the mammalian EGF receptor known as ErbB1, which triggers off a signal that ultimately activates sensory neurons and the perception of pain. In this case, long-lasting pain. Why long-lasting? No doubt to discourage predators from having another go. Perhaps, too, to give the ants sufficient time to make a run for it. <p>Here we have a startling example of adaptation where a creature mimics a model that belongs to its predator (here EGF) and promptly uses it to put its predator in danger - a form of mimicry that has been called Gilbertian mimicry. Of course, <em>M.gulosa</em> are far from the only living organisms to use mimicry for their survival. It is just another glorious example of time and biology working in unison to weave very specific needs into an existing tapestry. <em><p>*read <a href="https://www.proteinspotlight.org/back_issues/183/">Protein Spotlight issue 183</a></em> <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Eagles D.A., Saez N.J., Krishnarjuna B. <em>et al</em>.<p> A peptide toxin in ant venom mimics vertebrate EGF-like hormones to cause long-lasting hypersensitivity in mammals<p> PNAS 2022, DOI: 10.1073/pnas.2112630119<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35131940&query_hl=3&itool=pubmed_docsum">35131940</a></dd><dd>2. Robinson S.D., Mueller A., Clayton D. <em>et al</em>.<p> A comprehensive portrait of the venom of the giant red bull ant, <em>Myrmecia gulosa</em>, reveals a hyperdiverse hymenopteran toxin gene family<p> Science Advances 2018, DOI: 10.1126/sciadv.aau4640<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=30214940&query_hl=3&itool=pubmed_docsum">30214940</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd></dd><dd>OMEGA-myrmeciitoxin(02)-Mg1a, <em>Myrmecia gulosa</em> (Red bulldog ant): <a href="http://www.uniprot.org/uniprot/P0DSL4">P0DSL4</a><br></dd>]]> </content></entry> <entry> <title>a shrewd tweak</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-258.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.922</id> <published>2023-05-24T09:14:39Z</published> <updated>2023-05-24T09:42:44Z</updated> <summary>The chairs were rickety. So I rummaged around the kitchen drawer, extracted an old knife and used its tip to drive a few screws back into the wood. The knife kept on losing grip and I kept on swearing. The fastest and least infuriating way to have done the job would have been to go down to the cellar and find a screwdriver. Both utensils can be used to drive in screws, but one has been intentionally manufactured to perform just that, simultaneously reducing the time and energy involved. Nature, too, has its screwdrivers. Given time and chance, it will always take the opportunity to select a commodity which will make things, if not easier, at least more in tune with what is needed. One example: ribosomes are huge molecular complexes whose role is to synthesize proteins in cells. Until recently, it was thought that all ribosomes were alike. A bit like kitchen knives. However, it turns out that some ribosomes differ slightly in their makeup and are found only in certain kinds of cell - presumably because they synthesize proteins particular to these cells. One such ribosome has been discovered in sperm cells, along with a protein known as large ribosomal subunit protein eL39-like*, or RPL39L.</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 chairs were rickety. So I rummaged around the kitchen drawer, extracted an old knife and used its tip to drive a few screws back into the wood. The knife kept on losing grip and I kept on swearing. The fastest and least infuriating way to have done the job would have been to go down to the cellar and find a screwdriver. Both utensils can be used to drive in screws, but one has been intentionally manufactured to perform just that, simultaneously reducing the time and energy involved. Nature, too, has its screwdrivers. Given time and chance, it will always take the opportunity to select a commodity which will make things, if not easier, at least more in tune with what is needed. One example: ribosomes are huge molecular complexes whose role is to synthesize proteins in cells. Until recently, it was thought that all ribosomes were alike. A bit like kitchen knives. However, it turns out that some ribosomes differ slightly in their makeup and are found only in certain kinds of cell - presumably because they synthesize proteins particular to these cells. One such ribosome has been discovered in sperm cells, along with a protein known as large ribosomal subunit protein eL39-like*, or RPL39L.</p></b> <div class="quoteleft">« Ribosomes are among the most fundamental complexes to be found in organisms. And with good reason: they are where cells synthesize proteins. They are themselves an assemblage of various proteins mingled with RNA, known as ribosomal RNA (rRNA). From bacteria to fungi, plants, insects and mammals, ribosomes are all built according to the same architectural plan: one large subunit, one small subunit, and a handful of rRNA. »</div> <p>Ribosomes are among the most fundamental molecular complexes to be found in organisms. And with good reason: they are where cells synthesize proteins. Ribosomes are themselves an assemblage of various proteins mingled with RNA, known as ribosomal RNA (rRNA). And yes, ribosomes need ribosomes to synthesize the proteins that are part of their own constitution. From bacteria to fungi, plants, insects and mammals, ribosomes are all built according to the same architectural plan: one large subunit, one small subunit, and a handful of rRNA. Prokaryotic ribosomes are composed of one large subunit, itself a complex of about 30 proteins and two rRNAs, and a small subunit of about 20 proteins and one rRNA. In eukaryotes, the large subunit is characteristically composed of 47 proteins and three rRNAs, and the small subunit of 33 proteins and one rRNA. <p>Uniting as many as 47 proteins and three rRNAs into one large ribosomal subunit - which does not fall apart and performs the multiple tasks involved in protein synthesis - demands careful assembly. Making a ribosome is like building a factory while also hiring employees to carry out different tasks. In eukaryotes, everything begins in the nucleolus, a region located within the cell nucleus that is dedicated to the first steps of ribosome formation. Here the rRNAs are prepared and added to pre-ribosomal proteins. Both the small and the large subunits then begin, independently, to migrate towards the cell cytoplasm, where they will finally bind to one another, ready to do their job. During their migration, the subunits slowly mature as the parts which make them up are folded, processed, rotated, checked and finally channelled through the nuclear membrane. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt258.jpg" alt="Sophie Taeuber-Arp"/><figcaption>LINES OF SUMMER (detail), 1942</figcaption><dd><br></dd> <figcaption>by Sophie Taeuber-Arp (1889-1943)</figcaption><dd><br></dd> </figure></div> <p>In ribosomes, each protein has a different role - as do the rRNAs. Certain proteins are needed to stabilize the overall architecture while others help the large and small subunits assemble, and of course you have the proteins that are involved in exporting the ribosome from the nucleolus to the cytoplasm in the first place. Then you need the proteins that take an active part in protein synthesis per se - a process so incredibly delicate and intricate, it takes any student days, if not weeks, to grasp. Briefly - so much so, it may seem criminal - to synthesize one protein sequence, ribosomes read and translate (into amino acids) genes from their mRNA. The required amino acids are taken from the cell cytoplasm by tRNAs and added, in the correct order, to a growing protein chain which protrudes from a spot on the large subunit of the ribosome. A spot known as the nascent polypeptide exit tunnel, or NPET. When the sequence is complete, the protein slips out of the NPET and is sent to where it is needed in the cell, or outside the cell. What do rRNAs do? Like proteins, certain RNAs also have roles. In particular, rRNAs help ribosomes assemble the amino acids in the correct order - which is of utmost importance. With all the molecules and the many steps involved in protein synthesis, needless to say, it is one of the most costly activities of a cell, lapping up over 70% of its energy! <div class="quoteright">« Recently, researchers discovered that the very end of NPET in mammalian sperm cells differs from its counterparts and seems to have become specialised. As in other cells, protein sequences are double-checked in sperm NPETs, but sperm NPETs also seem to keep an extra good look out for proteins that are essential for sperm function. This would imply that sperm NPETs do not serve the exact same purpose as NPETs in other ribosomes, which turns out to be the case. »</div> <p>Around the NPET, ribosomes do an extra bit of quality checking, to make sure that the genes have been correctly read and their sequence properly assembled. If they have not, the faulty nascent chain is directed towards another part of the cell where it is disposed of. Recently, researchers discovered that the very end of NPET in mammalian sperm cells differs from its counterparts and seems to have become specialised. As in other cells, protein sequences are double-checked in sperm NPETs, but sperm NPETs also seem to keep an extra good look out for proteins that are essential for sperm function. This would imply that sperm NPETs do not serve the exact same purpose as NPETs in other ribosomes, which turns out to be the case. A protein known as RPL39 is usually located in NPETs where it forms part of the wall. In mammalian sperm, RPL39 has been replaced by a paralog, termed RPL39L. <p>RPG39L illustrates well the advantage of heterogenous ribosomes. Though RPL39L and its paralog RPL39 differ by only three amino acids, it is enough to impart to RPL39L roles that are advantageous to sperm. What is more, RPL39L and RPL39 are not interchangeable as is often the case with paralogs, further suggesting that RPL39L is cell-specific. RPL39L seems to have been tweaked to monitor the well-being of sperm in particular. In which way? Sperm motility requires a lot of energy. Few cells need to travel so far - what is more by their own means - to reach their destination. Such a trip requires energy, or ATP, which is produced by a cell's mitochondria. It so happens that RPL39L has a role in mitochondrion formation. In its absence, the organelles are malformed and sperm motility is defective. This could be explained by a role for RPL39L in double-checking the correct formation of mitochondrial proteins in the NPET. Moreover, RPL39L also seems to be involved in the faithful assembly of the large ribosomal subunit which, besides quality checking, is paramount to protein synthesis. <p>At the very heart of what could be defined as life, ribosomes represent the elemental passage from DNA to protein. The need for protein is unending within any living organism as each of our activities - visible or invisible - requires it. Cell homeostasis, on which life depends, relies on protein homeostasis. So, too, does sperm motility, and hence fertility. If sperm are unable to wriggle and swim because their flagella are not beating properly, they will never reach their destination. Or if they do, they may not have the wherewithal to fight and forage their way through the egg's coat and fertilize it. RPL39L could therefore constitute a therapeutical target to help counter infertility - at least the type of infertility caused by sperm that lack stamina. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Li h., Huo Y., He X. et al.<p> A male germ-cell-specific ribosome controls male fertility<p> Nature 612:725-731(2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=36517592&query_hl=3&itool=pubmed_docsum">36517592</a></dd><dd>2. Zou Q., Yang L., Shi R. et al.<p> Proteostasis regulated by testis-specific ribosomal protein RPL39L maintains mouse spermatogenesis<p> iScience 2021 Oct 30;24(12):103396<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=34825148&query_hl=3&itool=pubmed_docsum">34825148</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd><em>* up to July 2023, the protein's name is : 60S ribosomal protein L39-like</em></dd> <dd></dd><dd>60S ribosomal protein L39-like / large ribosomal subunit protein eL39-like, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q96EH5">Q96EH5</a><br></dd><dd>60S ribosomal protein L39-like / large ribosomal subunit protein eL39-like, <em>Mus musculus</em> (Mouse): <a href="http://www.uniprot.org/uniprot/Q9CQD0">Q9CQD0</a><br></dd>]]> </content></entry> <entry> <title>the slime inside us</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-257.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.921</id> <published>2023-04-21T09:46:56Z</published> <updated>2023-05-16T08:41:43Z</updated> <summary>When I was small, I used to visit an elderly lady who lived next door to us. With her, I would make rice-filled frogs. The kind you can fling from one end of a room to land flat, with a plod and no bounce, onto the arm of a chair or the back of a sofa. In the 1970s, these colourful frogs haunted every household in the UK. As I painstakingly cut out frog-shaped pieces of paisley-patterned material, Lady Clarke, as she was called, used to tower over me, observing my every move with a drop always hanging off the end of her nose. I would sit there terrified that it would lose grip and drip on to me. But it never did. It just wobbled, menacingly, until it was wiped away with a handkerchief Lady Clarke kept tucked up one of her sleeves. That drop was mucus. Besides exuding from our nose, especially when we have a cold or when we get old, mucus lines the mucous membranes of our body, where it keeps things lubricated and, generally, healthy. Mucus is composed of a lot of water and several macromolecules, among them glycoproteins that carry sialic acid. Why sialic acid? Because it helps to keep pathogens away. And how does it get there? By way of sialyltransferases.</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 I was small, I used to visit an elderly lady who lived next door to us. With her, I would make rice-filled frogs. The kind you can fling from one end of a room to land flat, with a plod and no bounce, onto the arm of a chair or the back of a sofa. In the 1970s, these colourful frogs haunted every household in the UK. As I painstakingly cut out frog-shaped pieces of paisley-patterned material, Lady Clarke, as she was called, used to tower over me, observing my every move with a drop always hanging off the end of her nose. I would sit there terrified that it would lose grip and drip on to me. But it never did. It just wobbled, menacingly, until it was wiped away with a handkerchief Lady Clarke kept tucked up one of her sleeves. That drop was mucus. Besides exuding from our nose, especially when we have a cold or when we get old, mucus lines the mucous membranes of our body, where it keeps things lubricated and, generally, healthy. Mucus is composed of a lot of water and several macromolecules, among them glycoproteins that carry sialic acid. Why sialic acid? Because it helps to keep pathogens away. And how does it get there? By way of sialyltransferases.</p></b> <div class="quoteleft">« We carry around a lot of mucus inside us. A 200 μm layer lines our intestine, forming about 2 m<sup>2</sup> of colonic slime... The slime is made up of various kinds of molecules like inorganic salts, antimicrobial enzymes, immunoglobulins and glycoproteins - and a whacking 94% of water. It is the water that gives mucus its gel-like nature: the oligosaccharide chains on glycoproteins sap up the water molecules, causing the mixture to expand and jellify, much like a dry sponge does when dipped into water. »</div> <p>Mucus is a protective lining for the epithelium and a very effective lubricant that keeps epithelial cells bathed in a soft gel-like ooze. It also constitutes a food supply for microbes, such as those that are part of our microbiome. In particular, mucus lines the respiratory, digestive and urogenital systems, but also structures in the visual and auditory systems, where it keeps pathogenic bacteria, virus and fungi away from epithelial cells they are only too keen to reach and infect. Our mucus - like those of many animals - does its job inside us. However, in other animals, mucus is found on the external side of the skin where it forms a protective film that spans the whole body - think about frogs, worms, fish, slugs and snails. <p>We carry around rather a lot of mucus inside us. A 200 μm layer lines our intestine, forming about 2 m<sup>2</sup> of colonic slime... The slime is made up of various kinds of molecules like inorganic salts, antimicrobial enzymes, immunoglobulins and glycoproteins - and a whacking 94% of water. It is the water that gives mucus its gel-like nature: the oligosaccharide chains on glycoproteins sap up the water molecules, causing the mixture to expand and jellify, much like a dry sponge does when dipped into water. In the respiratory tract, foreign material is rapidly drenched in mucus as it is driven by cilia into the pharynx, where a cough or a sneeze will do the rest. The various shades of yellow cum green we observe are the signature of pathogenic infection. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt257.jpg" alt="Emily Harvey"/><figcaption>etched linoprint by Emily Harvey</figcaption><figcaption><a href="https://thecuriousprintmaker.co.uk/"> thecuriousprintmaker.co.uk </a></figcaption><dd><br></dd><figcaption>courtesy of the artist</figcaption><dd><br></dd> </figure></div> <p>Where do the components that compose mucus come from? From goblet cells, so named for their goblet-like shape - large and round at their base, and long and narrow from the middle up - with an apical crown that is folded many times to multiply their surface. Goblet cells are an integral part of mucus-lined epithelia where they are scattered among other epithelial cells. Their nucleus is forced into the basal end of the cell body. Their Golgi apparatus - where (to cut a long story short) proteins are packed away into vesicles ready for secretion - is pushed into the middle of the cell, while the apical end is crammed with secretory vesicles full of glycoprotein, or mucin, that release their contents into, say, the intestinal lumen. Bring in some water, mix everything and you have mucus - which is repaired and replaced on a continuous basis. <div class="quoteright">« It is the sialic acid in mucus that creates the protective barrier between pathogens and epithelial cells. Sialic acid can affect a cell's behaviour and is involved in many important biological processes such as cell recognition, cell adhesion, cell signal transduction, protein folding..., and of course pathogen infection and mucus integrity. »</div> <p>It is the sialic acid in mucus that creates the protective barrier between pathogens and epithelial cells. Sialic acids are negatively charged 9-carbon monosaccharides that are popped onto the carbohydrate chains of glycoproteins. The most common sialic acid is N-acetylneuraminic acid. Sialic acid can affect a cell's behaviour and is involved in many important biological processes such as cell recognition, cell adhesion, cell signal transduction, protein folding..., and of course pathogen infection and mucus integrity. To date, about 50 different sialic acids have been described, all of which are derived from a molecule of neuraminic acid and are expressed at different stages of an organism's development or in different tissues. <p>Sialyltransferases are transmembrane enzymes, located in the Golgi apparatus and are responsible for transferring sialic acid to glycoproteins. There are about 20 different kinds of sialyltransferases, which have been classified into types according to where exactly sialic acid is added to glycoconjugates - and how. In particular, goblet cell sialyltransferases belong to a type known as alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1, or more simply ST6, which refers to the type of glycosidic bond involved. Like all sialyltransferases, the enzymes have an N-terminal cytoplasmic tail, a transmembrane domain and a large COOH-terminal catalytic domain that protrudes into the Golgi lumen. The catalytic domain has four conserved motifs which, collaboratively, bind sialic acid and then transfer it to glycoproteins. This process known as sialylation seems to take place when goblet cells sense the presence of microbial pathogens in the mucus. <p>Consequently, not only is sialylation important in discouraging mucous pathogens but it is, inevitably, involved in mucus homeostasis and hence human health, not to mention the well-being of our microbiome. The intestinal lumen, mucus and commensalism are all part of one system, whose parts are intricately intertwined and depend on one another. A deficiency in sialylation creates an imbalance in mucus homeostasis and is thought to bring about diseases such as inflammatory bowel disease (IBD) which inflicts an estimated 10 million people worldwide. As sialyltransferases are involved in vital processes such as cell recognition and cell adhesion, problems with sialylation could also play a part in tumour cell migration, i.e. metastases. In both cases, treatments that specifically affect sialyltransferase function could therefore be of interest. Certainly, in retrospect, it is with far greater respect that I remember the drop on the end of Lady Clarke's nose. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Yao Y., Kim G., Shafer S., et al.<p> Mucus sialylation determines intestinal host-commensal homeostasis<p> Cell 185:1172-1188(2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35303419&query_hl=3&itool=pubmed_docsum">35303419</a></dd><dd>2. Li Y., Chen X.<p> Sialic acid metabolism and sialyltransferases: natural functions and applications<p> Applied Microbiology & Biotechnology 94:887-905(2012)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=22526796&query_hl=3&itool=pubmed_docsum">22526796</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q9NSC7">Q9NSC7</a><br></dd>]]> </content></entry> <entry> <title>in the beginning</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-256.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.920</id> <published>2023-03-18T10:56:56Z</published> <updated>2023-03-18T11:21:09Z</updated> <summary>It is one of the many mysteries of our existence. How does life begin? What gives the first nudge? Is there, for that matter, a primordial poke? Over the millennia, scholars have tried to define the actual notion of life as a whole - which may seem obvious to some, but just sit down for a while and give it a thought. How are creatures made? How do they begin? What, for instance, goes on inside a womb? Theories varied according to the knowledge of the times, and explanations shifted from the near mystical to the anatomical, closely followed by the cellular until the 1980s, when - thanks to the rise of novel technologies - researchers could consider embryology at the level of the molecular. Though we are still really asking the same questions, what we know about the making of life has been dramatically fine-tuned and we now delve into the minute, wondering which molecules drive cells to become one part of an organism or another. What factors kickstart the process of a cell's fate? Today, we have part of the answer: the tetra-peptide repeat homeobox proteins. Transcription factors without which the very first embryonic cell divisions would not occur.</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>It is one of the many mysteries of our existence. How does life begin? What gives the first nudge? Is there, for that matter, a primordial poke? Over the millennia, scholars have tried to define the actual notion of life as a whole - which may seem obvious to some, but just sit down for a while and give it a thought. How are creatures made? How do they begin? What, for instance, goes on inside a womb? Theories varied according to the knowledge of the times, and explanations shifted from the near mystical to the anatomical, closely followed by the cellular until the 1980s, when - thanks to the rise of novel technologies - researchers could consider embryology at the level of the molecular. Though we are still really asking the same questions, what we know about the making of life has been dramatically fine-tuned and we now delve into the minute, wondering which molecules drive cells to become one part of an organism or another. What factors kickstart the process of a cell's fate? Today, we have part of the answer: the tetra-peptide repeat homeobox proteins. Transcription factors without which the very first embryonic cell divisions would not occur.</p></b> <div class="quoteleft">« Zygotes are totipotent cells. That is to say that they have the power to build a whole organism, with all its different tissues and all their different kinds of cells. This 'potency' cannot only be explained by the DNA held within the zygote's nucleus because the great majority of the cells in our body carry the exact same genome in their nucleus too. Yet, try as you wish, they are unable to create another you. So there must be something else going on. Cells are selected to become muscle cells or brain cells. They are driven to a certain fate. This is the essence of embryology. »</div> <p>Recordings of an interest in human development date back to Ancient Egypt. By the 18th century - and many dissections and theories later - two opposing schools had been established: the preformationists and the epigenesists. The preformationists believed that embryos were miniature completed organisms that floated in the maternal egg or in the sperm. They were the creation of God and, when their time came, they simply unfolded to grow into their mature size. The epigenesists, on the other hand, believed that organisms developed progressively from an egg, itself newly produced from unorganised material. It would take microscopes, and the science of cell biology followed by that of molecular biology to finally grasp the subtle intricacies of embryogenesis we are aware of today. To cut a labyrinthine story short, upon fertilization by a sperm, the maternal egg becomes what is known as a zygote. A zygote is the very first cell each one of us emerged from to form a skeleton, a heart, a brain, a stomach, an immune system, feelings, thoughts, memories, creativity, language, eyes, a nose, a mouth, two legs, ten fingers and ten toes. The epigenesists were on the right track. <p>Zygotes are totipotent cells. That is to say that they have the power to build a whole organism, with all its different tissues and all their different kinds of cells. This 'potency' cannot only be explained by the DNA held within the zygote's nucleus, i.e. its genome, because the great majority of the cells in our body carry the exact same genome in their nucleus. Yet, try as you wish, they are unable to create another you. So there must be something else going on. Cells are selected to become muscle cells or brain cells. They are driven to a certain fate. This is the essence of embryology. What drives this are molecular factors that regulate the transcription of genes and their translation into proteins - gradually urging a cell into one direction or another by switching sets of genes on or off. Little by little, division after division, cells will lose their potency, to become 'soldier' cells that are part of only one type of tissue: the brain, the blood, muscle and so on. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt256.jpg" alt="Imprimerie Pichot"/><figcaption>"Paysage de la Creuse" (1925)</figcaption><dd><br></dd><figcaption>Félix Vallotton</figcaption><dd><br></dd> </figure></div> <p>In fact, the totipotency of a zygote is lost very quickly. By the time the embryo is only composed of 4 cells, each cell is already beginning to head in a particular direction. By the eight-cell stage, taken independently, not one of the cells would be able to develop into a whole organism anymore. Once an organism is fully formed, most of its cells are only able to divide into a cell of the same nature: a muscle cell will give rise to another muscle cell for instance. Certain special cells, however, do preserve a certain potency, albeit diminished. These are known as stem cells. Blood-forming stem cells, for example, give rise to different types of blood cell. In brief, the fate of a cell can be seen as the expression, or not, of different sets of genes whose products may also go on to encourage the expression of others, or not. <p>One of the most stunning - yet invisible - cascades to occur must undoubtedly be the one that begins immediately after the formation of a zygote. First, though, the zygote needs to be given a small shove. Something has to ignite the flame and set things off. This moment has been called 'zygote genome activation', or ZGA. Literally, the zygote's genome is stirred by transcription factors (TFs). The moment a zygote is formed, TFs leap into action to stimulate the expression of specific genes which, in turn, will stimulate the expression of others, thus kickstarting the development of an embryo and then the foetus. ZGA thus marks the very first transcription event in a new life. <div class="quoteright">« One of the most stunning cascades to occur must be the one that begins immediately after the formation of a zygote. First, though, the zygote needs to be shoved - a moment called 'zygote genome activation', or ZGA. Literally, the zygote's genome is stirred by transcription factors (TFs) that leap into action to stimulate the expression of specific genes which, in turn, will stimulate the expression of others. The development of an embryo may begin. ZGA thus marks the very first transcription event in a new life. »</div> <p>Yes, but where do these factors come from, and what makes then burst into life - so to speak. As an illustration, let us consider three factors known as tetra-peptide repeat homeobox proteins: TPRXL, TPRX1 and TPRX2. All three TPRXs are transcription factors which are highly expressed during the early stages of ZGA, each binding to specific regulatory DNA sequences on the promotor of genes directly involved in the event. TPRXL is the first to act as it is produced from dormant maternal transcripts already present in the egg. TPRX1 and TPRX2 appear shortly after, probably generated once the zygote is formed. Together, TPRXL, 1 and 2 ensure that ZGA actually occurs and that the early form of the embryo at the stage of a blastocyst is correctly formed, thereby ensuring correct implantation in the uterus. Though TPRX are far from the only TFs to be activated at this critical moment of embryo development, without them, ZGA does not happen. <p>In a way, TPRX factors are among those that mark the beginning of embryonic cell decline in potency. This may sound gloomy, but this critical tipping point is of great interest to researchers. Understanding ZGA in detail, getting to know - intimately - the factors that provoke it, grasping the notion of totipotency and pluripotency in molecular terms are studies that could help resolve some cases of infertility, as well as giving insight into the very early steps of embryogenesis and the possible onset of developmental disorders. What, too, if researchers were able to master human cells and use them to produce transplants - a heart for example. Science fiction? Not really. Remember Dolly? Studies of the like, however, are strongly discouraged on human embryos because of severe restrictions with respect to ethical considerations. And thankfully so, no doubt. It is about life, and its onset. Deeply entrancing, and yet disconcerting. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Zou Z., Zhang C., Wang Q., et al.<p> Translatome and transcriptome co-profiling reveals a role of TPRXs in human zygotic genome activation<p> Science 378: abo7923-abo7923 (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=36074823&query_hl=3&itool=pubmed_docsum">36074823</a></dd><dd>2. Mazid M.A., Ward C., Liu C., et al.<p> Rolling back human pluripotent stem cells to an eight-cell embryo-like stage<p> Nature 605: 315-324 (2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35314832&query_hl=3&itool=pubmed_docsum">35314832</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Tetra-peptide repeat homeobox-like protein, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q17RH7">Q17RH7</a><br></dd><dd>Tetra-peptide repeat homeobox protein 1, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q8N7U7">Q8N7U7</a><br></dd><dd>Tetra-peptide repeat homeobox protein 2, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/P0DV77">P0DV77</a><br></dd>]]> </content></entry> <entry> <title>on the end of a leash</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-255.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.919</id> <published>2023-02-17T13:20:31Z</published> <updated>2023-03-18T11:15:32Z</updated> <summary>It has been a long time since I saw a plug hanging from the side of a bathtub. Remember the small triangular ring the chain dangled from, and the actual plug at the other end - usually a piece of black and slimy rubber that fitted perfectly into the plug hole. As a child, the perfection of the fit used to fascinate me and I would sit in the bath, pulling the plug out and pushing it back in again, fighting against the swirl and dynamics of flowing water. The system is straightforward enough. If you do not want the bath to empty, take something large, strong and watertight to fill the hole. You may think we are the inventors of the plug, but we are not. Filamentous fungi have been using the same kind of approach for millions of years to obstruct large holes, or septal pores, whose role is to let cytosol migrate from one part of the fungus to another. Sometimes it is necessary to seal the pores off, however. This happens thanks to organelles known as Woronin bodies which, just like the bath plug, are tethered close by. </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>It has been a long time since I saw a plug hanging from the side of a bathtub. Remember the small triangular ring the chain dangled from, and the actual plug at the other end - usually a piece of black and slimy rubber that fitted perfectly into the plug hole. As a child, the perfection of the fit used to fascinate me and I would sit in the bath, pulling the plug out and pushing it back in again, fighting against the swirl and dynamics of flowing water. The system is straightforward enough. If you do not want the bath to empty, take something large, strong and watertight to fill the hole. You may think we are the inventors of the plug, but we are not. Filamentous fungi have been using the same kind of approach for millions of years to obstruct large holes, or septal pores, whose role is to let cytosol migrate from one part of the fungus to another. Sometimes it is necessary to seal the pores off, however. This happens thanks to organelles known as Woronin bodies which, just like the bath plug, are tethered close by.</p></b> <div class="quoteleft">« Filamentous fungi are long and filament-like, and divided into compartments by septa, themselves an extension of the cell membrane - which sounds as though they have two separate cells. However, parts of the cytosol can migrate freely through the septa thanks to large non-selective septal pores - an odd circumstance when the integrity of a cell does seem to be the best way to preserve life. »</div> <p>Filamentous fungi are so named because their cells - or hyphae - are long and filament-like. Hyphae are divided into compartments by septa, themselves an extension of the cell membrane. This sounds as though they have two separate cells, but it is not quite the case because indistinct parts of the cytosol can migrate freely through the septa, from compartment to compartment, thanks to large non-selective septal pores. Organelles as big as the nucleus can slip through. This may sound odd when the integrity of a cell does seem to be the best way to preserve life but it is a way of having the characteristics and benefits of a multicellular organism while keeping things relatively simple. There is a downside, however. If the cell membrane of a compartment is damaged, the cytosol will leak out unrestrained while probably letting unwanted matter drift in - unless septal pores are rapidly blocked. This is exactly what occurs. <p>Septal pores situated close to a recent wound are obstructed by organelles known as Woronin bodies (WB) - named after the Russian mycologist Mikhail Woronin (1838-1903) who was the first to describe them. Just big enough to be seen through a light microscope, WBs are very similar to peroxisomes. Peroxisomes are small single-membrane organelles that have a crystallized enzyme core and are found in virtually all eukaryotic cells where they are involved in a variety of metabolic reactions. WBs are only present in filamentous fungus, however, and the crystallized enzyme core is formed by a protein known as Woronin body major protein, or HEX-1. Why HEX-1? Because in <em>Neurospora crassa</em>, where this peculiar organelle was first observed, the protein spontaneously assembles into hexagonal crystals forming a matrix of oligomers. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt255.jpg" alt="Imprimerie Pichot"/><figcaption>"Le Ballon"</figcaption><figcaption>Imprimerie Pichot, Paris (1883)</figcaption><figcaption>perhaps by Jules Chéret? (1836-1932)</figcaption><dd><br></dd> </figure></div> <p>HEX-1 seems to be unique to filamentous fungus. It has a peroxisome-targeting motif at its C-terminal, which is thought to target the protein to a peroxisome. Once inside, phosphorylation of HEX-1 triggers the self-assembly of HEX-1 monomers to form a large crystalline matrix which is not only stable but also particularly rigid. This initial formation would then bud from the peroxisome to form an actual Woronin body. Stability and especially rigidity are ideal properties for WBs to act as septal pore plugs - which need to be larger than the hole they must fill besides being inflexible. Other more 'flexible' organelles could cave in and gradually ease their way through septal pores under the pressure of the cytosolic flow caused by a wound. <p>Septal plugs cannot be left to float around freely, however. In hyphae, cytosol is continuously passing from one side of a compartment to another, creating a current strong enough to drag with it WBs - or any other cellular entity for that matter - towards septal pores. This would undoubtedly clog the pores which would compromise the necessary communication between compartments, thus harming the fungus. Like buoys in a harbour, WBs need to be tethered to something stable as they await to be used. A closer look at these peculiar organelles showed that WBs are indeed attached to the cell cortex - a region that lines the cell membrane on the cytoplasmic side - on the end of a long elastic tether, either close to the rim of septal pores, or much further away as is the case in <em>N.crassa</em> for instance. The long leash turns out to be formed by a protein (named leashin) where one end is associated with the cell cortex and the other is linked to a WB. <div class="quoteright">« It is extraordinary that such a simple and seemingly obvious system has been thought up by cells. When hyphae are wounded, cytosol leaks out of the wound in a gush. The strength of the gush is sufficient to drive WBs towards the closest septal pores to seal them off. Many scientists, however, think that sealing off is not merely passive. »</div> <p>It is extraordinary to realise that such a simple and seemingly obvious system to plug holes has been thought up by cells. In the wild, filamentous fungi are prone to damage as many species grow in forests. In fact, they seem to thrive where there have been forest fires - an event which is becoming more and more frequent with climate change. When hyphae are wounded, cytosol leaks out of the wound in a gush. The strength of the gush is sufficient to drive WBs towards the closest septal pores to seal them off. Many scientists, however, think that sealing off is not merely passive since septal pores are sometimes also plugged in the absence of wounds, as presumably they must be unplugged too. This would imply that there is some kind of active regulation too, which would be used to regulate communication between compartments - a little like creating temporary cells. <p>Filamentous fungi seem to have found a way of remaining unicellular while establishing a near multicellular status with their septa and septal pores. Several filamentous fungi are pathogenic to plants and animals, causing serious mycoses or respiratory problems in humans for example, or killing off plants. Since the formation of Woronin bodies depends on the presence of HEX-1, the protein could present an ideal therapeutic target for diseases inflicted by filamentous fungi in humans, and it could also be used to make plant fungicides. In the meantime, is it not wonderful to know that, millions of years ago, Nature imagined what look like sophisticated balloons tied to the end of a tethered string to regulate the stream of life within cells? <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Steinberg G., Harmer N.J., Schuster M. et al.<p> Woronin body-based sealing of septal pores<p> Fungal Genetics and Biology 109:3-55(2017)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=29107012&query_hl=3&itool=pubmed_docsum">29107012</a></dd><dd>2. Jedd G., Chua N.-H.<p> A new self-assembled peroxisomal vesicle required for efficient resealing of the plasma membrane<p> Nature Cell Biology 2:226-231(2000)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10783241&query_hl=3&itool=pubmed_docsum">10783241</a></dd><dd>3. Beck J., Echtenacher B., Ebel F.<p> Woronin bodies, their impact on stress resistance and virulence of the pathogenic mould <em>Aspergillus fumigatus</em> and their anchoring at the septal pore of filamentous Ascomycota<p> Molecular Microbiology 89:857-871(2013)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=23869404&query_hl=3&itool=pubmed_docsum">23869404</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Woronin body major protein, <em>Neurospora crassa</em>: <a href="http://www.uniprot.org/uniprot/P87252">P87252</a><br></dd>]]> </content></entry> <entry> <title>on a tightrope</title> <link rel="alternate" type="text/html" href="https://web.expasy.org/spotlight/back_issues/notifications/sptlt-notification-254.html" /> <id>tag:web.expasy.org,2023:/spotlight//2.918</id> <published>2023-01-23T14:46:43Z</published> <updated>2023-02-14T11:09:21Z</updated> <summary>Too much of anything is never good. Excess alcohol, and our faculties are impaired. Excess heat, and drought spreads. Excess cold, and vineyards die. Too much, too, of what is paradoxically essential to life frequently turns out to be toxic. Consider oxygen, iron, zinc or vitamins to name but four. Though we may be acquainted with the symptoms of what 'too much' entails, these are merely the superficial echo of cells under stress. Over the aeons, and throughout the living kingdom, organisms have had to deal with periodical over-abundances of many things. While selecting systems to use them in small doses, they promoted others to keep them in check. As an illustration, iron is vital for ferrying oxygen in organisms, and it is crucial in DNA synthesis, DNA repair and other fundamental cellular processes. Yet, too much iron will kill a cell - a process known as ferroptosis. Though this may be an ideal way of ridding a tissue of unhealthy cells, alternative processes have also evolved to stabilise things and prevent ferroptosis. One of these processes involves a protein known as ferroptosis suppressor protein 1, or FSP1.</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>Too much of anything is never good. Excess alcohol, and our faculties are impaired. Excess heat, and drought spreads. Excess cold, and vineyards die. Too much, too, of what is paradoxically essential to life frequently turns out to be toxic. Consider oxygen, iron, zinc or vitamins to name but four. Though we may be acquainted with the symptoms of what 'too much' entails, these are merely the superficial echo of cells under stress. Over the aeons, and throughout the living kingdom, organisms have had to deal with periodical over-abundances of many things. While selecting systems to use them in small doses, they promoted others to keep them in check. As an illustration, iron is vital for ferrying oxygen in organisms, and it is crucial in DNA synthesis, DNA repair and other fundamental cellular processes. Yet, too much iron will kill a cell - a process known as ferroptosis. Though this may be an ideal way of ridding a tissue of unhealthy cells, alternative processes have also evolved to stabilise things and prevent ferroptosis. One of these processes involves a protein known as ferroptosis suppressor protein 1, or FSP1.</p></b> <div class="quoteleft">« Over the aeons, and throughout the living kingdom, organisms have had to deal with periodical over-abundances of many things. While selecting systems to use them in small doses, they promoted others to keep them in check. Iron, as an example, is vital for ferrying oxygen in organisms, and it is crucial in DNA synthesis, DNA repair and other fundamental cellular processes. Yet, too much iron will kill a cell - a process known as ferroptosis. »</div> <p>Ferroptosis is defined as the death of a cell brought about by an overwhelming presence of iron. Though iron is vital for all species - as it is required to transport and deliver oxygen to organs, to ferry electrons in mitochondria or as a cofactor for instance - too much of it can be toxic as it can hinder a cell's antioxidant capacity. This means that noxious 'lipid reactive oxygen species' begin to accumulate, ultimately leading to oxidative cell death where, in the case of ferroptosis, plasma membranes typically rupture and mitochondria shrink while the cells, swell. This is unlike other programmed cell deaths, such as apoptosis for instance where cells typically bleb and diminish in size, which is why scientists regard ferroptosis as a category apart. <p>What exactly is meant by 'oxidative cell death'? In the case of ferroptosis, this implies lipid peroxidation that is driven by an iron-containing enzyme lipoxygenase. Lipid peroxidation involves the degradation of lipids caused by the addition of molecular oxygen which attacks their carbon-carbon double bonds. As the main constituent of plasma membranes are phospholipids, these present an ideal target for peroxidation modification which interferes not only with the assembly of plasma membranes but also with its structure and dynamics. As a result, if nothing is done to counter peroxidation, plasma membranes are damaged and the cell eventually dies. <div class="blogimgcenter"><figure><img src="/spotlight/images/sptlt254.jpg" alt="Helen Phillips"/><figcaption>"Danseuse, by Helen Phillips</figcaption><figcaption><a href="https://www.annexgalleries.com/">The Annex Galleries</a></figcaption><figcaption>, Santa Rosa, California</figcaption><dd><br></dd> </figure></div> <p>Molecules known as antioxidants regulate the level of oxidation in a cell. CoQ10 is one. When CoQ10 was first discovered, it was called 'vitamin Q10', where 'Q' stands for 'quinone' and '10' refers to the number of isoprenyl chemical subunits in the molecule's tail. In time, vitamin Q10 was renamed 'ubiquinone' because of its ubiquitous presence in lipid membranes. CoQ10 is a lipid-soluble antioxidant meaning that it can slip into the plasma membrane of cell organelles, such as the mitochondrion, the endoplasmic reticulum or the Golgi apparatus. Here, ubiquinone must remain in a reduced state - CoQ10H2 also known as ubiquinol - so as to halt the propagation of lipid peroxides. How is ubiquinol kept in a reduced state in animals? Thanks to FSP1. <p>Ferroptosis suppressor protein 1 (FSP1) is an enzyme or, more specifically, a CoQ10 plasma membrane oxidoreductase. This is where the 'Co' springs from in CoQ10 since the molecule is also referred to as 'coenzyme Q10' as it is required by FSP1 for its catalytic activity. Like its coenzyme, FSP1 is also present in plasma membranes and probably targeted there thanks to a post-translational modification known as myristoylation which is the addition of a long fatty acid at the enzyme's N-terminus. Myristoylation not only directs FSP1 towards plasma membranes but also helps it squeeze between the phospholipids. So now we have CoQ10 and FSP1 in the plasma membrane - and all we need to suppress ferroptosis is a source of hydrogen which is supplied by the omnipresent and universal cofactor NADPH. Thanks to NADPH, FSP1 can produce the reduced form of ubiquinone, CoQ10H2 or ubiquinol, which is then armed to fight lipid peroxidation. <div class="quoteright">« Life tiptoes along a narrow tightrope. From an evolutionary point of view, the involvement of a component as biologically vital as iron in ferroptosis is intriguing. Iron has an essential role in life that dates back billions of years. When oxygen started to accumulate in the Earth's atmosphere and organisms began to use oxygen to drive many of their vital processes which were already dependent on iron, they were concomitantly building one of Nature's conundrums: she was going to have to find a way of keeping toxicity at bay. »</div> <p>Having sorted out this rather complex biochemistry, another molecule popped up: vitamin K. Vitamin K, like CoQ10, belongs to the family of quinones and is prescribed in substantial doses to patients taking warfarin, a popular blood thinner. Why? Because vitamin K counters warfarin poisoning - but no one really understood why. It turns out that vitamin K is also involved in suppressing ferroptosis. Indeed, vitamin K and CoQ10 happen to share similar structural properties. Consequently, vitamin K can take the place of CoQ10 in FSP1, where it is reduced. The resulting reduced vitamin K (VKH2), like CoQ10H2 is also a potent inhibitor of lipid peroxidation. Scientists then realised that the reduction of vitamin K led by FSP1 is also responsible for the effect vitamin K has against warfarin poisoning. <p>Cells are able to cope with certain levels of lipid peroxidation; it just must never reach levels that become detrimental to the cells. It all comes down to equilibrium. This said, FSP1 is not the only enzyme involved in taming ferroptosis; there are other pathways too, each of which seem to supplement the other. In recent years, medical scientists have taken a growing interest in ferroptosis as it seems to be at the heart of neurodegenerative diseases such as Alzheimer's and Parkinson's but also diseases like cancer. Promoting ferroptosis could kill cancer cells for example while, in neurodegenerative diseases, checking ferroptosis could keep neurons alive. This would make FSP1 an ideal therapeutic target besides proving, perhaps, to be a good biomarker. <p>Life certainly tiptoes along a narrow tightrope. From an evolutionary point of view, the involvement of components as biologically vital as iron and vitamin K in ferroptosis is intriguing. Iron has an essential role in life that dates back billions of years. When oxygen started to accumulate in the Earth's atmosphere and organisms began to use oxygen to drive many of their vital processes which were already dependent on iron, they were concomitantly building one of Nature's conundrums: she was going to have to find a way of keeping toxicity at bay. In this light and long before the existence of FSP1, vitamin K could actually be the most ancient member of anti-ferroptotic quinones since ferroptosis is a cell-death mechanism that has been conserved from prokaryotes to plants and mammals. Fascinating. <div class="blogfooter"><dl><dt><strong>References</strong></dt><dd>1. Mishima E., Ito J., Wu Z., et al. <p> A non-canonical vitamin K cycle is a potent ferroptosis suppressor<p> Nature 608: 778-783(2022)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=35922516&query_hl=3&itool=pubmed_docsum">35922516</a></dd><dd>2. Doll S., Porto Freitas F., Shah R., et al.<p> FPS1 is a glutathione-independent ferroptosis suppressor<p> Nature 575: 693-698(2015)<p> PMID:<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=31634899&query_hl=3&itool=pubmed_docsum">31634899</a></dd></dl></div> ]]> <![CDATA[<dt><strong><a href="http://www.uniprot.org/">UniProt</a> cross references</strong></dt><dd>Ferroptosis suppressor protein 1, <em>Homo sapiens</em> (Human): <a href="http://www.uniprot.org/uniprot/Q9BRQ8">Q9BRQ8</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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