Talk:Serpin

response to ideas, current state of play
All structural figures now added - on reflection I actually think that a TBG image would be better under a TBG page. Table reasonably well referenced Catalytic mechanism figure adapted and added as suggested. I have asked a colleague for an attractive cell biology figure to go at the top of the page More references added through out and some cleanup and wikifying performed (thanks to Arcadian and Kjaergaard) Have some ideas for additional sections - serpin folding, comment on exception to Anfinsens etc, illustrate phylogeny of superfamily, section on fly serpins and worm serpins.

Jcwhizz 09:39, 12 March 2007 (UTC)

Suggested additions to make before request general review
Polymer picture - combine with delta picture (in progress) Add "disease caused by deficiency" to human serpin list Add figure illustrating key serpin regions that are often mutated in human disease (Breach, shutter). Perhaps put in figure with conserved residues highlighted (or is this too specialised?) Expand polymer section and make more general linkages with protein misfolding Illustrate non-inhibitory section with picture of TBG, ligand and binding site highlighted. General cleanup, add a few more references, PMIDs where possible. Any other suggstions? Jcwhizz 00:59, 11 March 2007 (UTC)

In my opinion, the broad content in the serpin page is now scientificaly accurate, up-to-date, reasonably concise and appropriately structured (I have to admit to some bias, however, having written some of it!). I feel that the only major omission is a picture of a model of a serpin polymer (which I am making). I think there is still quite a bit of stylistic correction and cleanup to do. Major references in the field have been added, however, secondary references should probably be added too? I think the time is right for some more general feedback from the MCB comunity, however, I'm unsure how to start the review process. Jcwhizz 09:42, 11 March 2007 (UTC)

Right now the article is very good on the structural stuff, but contains very little about other aspects about serpins. This bias is probably related to the interests of the contributors. We need a beautiful picture to place in the top of the page to catch the interest of the readers. I think we need to show the catalytic cycle of serine proteases as well, showing explicitly where it is interupted. And I think the table should have the protein names as the first column, rather than the genes, since that are the names they are primarily known by... Kjaergaard 10:17, 11 March 2007 (UTC)

Agree with you on the structural bias (have to confess thats my area) and the catalytic cycle. However, there is a huge effort in the serpin community to stop using the "old" serpin names (which and to use the proper nomenclature SERPINA1 etc as the protein name - I will edit the Gene name to read Protein name (which is actually correct).  I'll have a think about a beautiful (non structural) picture.

210.49.179.196 11:02, 11 March 2007 (UTC)

What do you think about a really attractively stained picture of a blood clot (appropriate given the large number of serpins involved in clotting / bleeding etc) or alternatively a white blood cell (rich in serpins) - not sure where to source these though as I don't have them myself. I have to confess I thought first about a nice picture of a serpin crystal - though on reflection I realised that possibly may be too structural...:) ?

Jcwhizz 11:29, 11 March 2007 (UTC)

And I'm pretty sure that PAI-1 doesn't inhibit plasmin directly. I don't know if you have a reference claiming this... Kjaergaard 10:20, 11 March 2007 (UTC)

Will check this out

210.49.179.196 11:02, 11 March 2007 (UTC)

Yup - my mistake - fixed

Jcwhizz 11:29, 11 March 2007 (UTC)

previous discussion
Serpin page coming together - some major and minor things to do. Major: 1) Add more figures (polymer). 2) More extensive referencing 3) Brief two liners about the function of each human serpin - for more in depth analysis should link to relevant pages 4) Section on serpin-enzyme complex uptake by LRP-related protein receptor. 5) Section on worm serpins

Minor Add PMID ids to references that do not have them Work out how to assign a unique number to a reference (i.e. so it is not repeated in the bibliography

Jcwhizz 05:26, 7 March 2007 (UTC)

What is the basis for saying that serpins are enzymes? As I understand it they are "suicide substrates". What reaction are they supposed to catalyze? Josh Cherry 23:15, 14 Jun 2004 (UTC)


 * In the strict sense of the word you're completely right. Perhaps we should revise nomenclature on this. By the way, how would you categorise these articles? JFW | T@lk  09:45, 15 Jun 2004 (UTC)

A topical serpin involved in malaria resistance - in mosquitoes!
The Monday, 24 October 2005 BBC News headline,

Malaria gene 'defends mosquitoes'

http://news.bbc.co.uk/1/hi/health/4370960.stm

...turns out to refer to this paper:

An immune-responsive serpin, SRPN6, mediates mosquito defense against malaria parasites

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16260729

The conclusion states that Anopheles stephensi SRPN6 is either directly or indirectly involved in the parasite-killing process, whereas Anopheles gambiae SRPN6 apparently acts further downstream on parasite clearance by promoting lysis.

(Mosquitoes with SRPN6 expression knocked out were ultra-susceptible to Plasmodium infection; steps are being taken to produce mosquitoes with a constitutively-active SPRN6 gene, to see what effect that has - immune mosquitoes in the wild would equal reduced Plasmodium transmission rates, until either the parasite or the insect evolved round it...)

Anyway, I just thought this might be germane to this article, but as this is the first time I've done anything on wikipedia, methought it better merely to mention it here so people can see what they think.

Cheers, Tommy B.

It might be more relevant to the Malaria article.... Kjaergaard 18:20, 15 April 2007 (UTC)

Thanks - have pasted it into the Talk:Malaria page, so people there can see what they thank. --Tommy B.

Lead suggestions
The lead has three functions. Firstly, the initial sentence should define the topic clearly and precisely without using too many technical terms. Secondly, the lead should introduce the topic and indicate why it is important. Thirdly, the lead should provide a brief summary of the main points in the article. The lead does an OK job of point one, but is still a bit short for points two and three. Aim for about three paragraphs? Tim Vickers 17:53, 28 July 2007 (UTC)

Hi Tim - good point - have expanded as suggested. Cheers James Jcwhizz 01:43, 29 July 2007 (UTC)

good article review
This is how the article, compares against the six good article criteria:


 * 1. Well written?:
 * "and inflammation respectively" needs comma before "respectively"

Done Jcwhizz 00:13, 4 August 2007 (UTC)


 * Sometimes a bit verbose -


 * "The interest in these molecules was initially sparked as a result of their" could be put more succinctly "Initially, research focused on their.."
 * "While the majority of serpins function to control key extracellular and intracellular proteolytic cascades,..." could be better as "While most serpins control proteolytic cascades,..."
 * "As a result of their involvement in controlling medically important processes such as coagulation and inflammation, there is considerable interest in serpin function and serpin deficiency." could be better as "As serpins control processes such as coagulation and inflammation, these proteins are the target of medical research."
 * "The study of serpinopathies is useful for understanding the generalities of protein misfolding, a process that underlies other important human diseases such as Alzheimer’s and prion disease." could be better as "Undertanding serpinopathies provides insights on protein misfolding in general, a process common to many human diseases, such as Alzheimer’s and CJD."
 * "it is postulated that serpins inhibit both classses" could be better as "serpins may inhibit both classes"
 * "Analysis of Caenorhabditis elegans serpins revealed that all nine serpin genes lacked signal sequences and these are therefore are proposed to be intracellluar" could be better as "As all nine serpins in Caenorhabditis elegans lack signal sequences, they are probably intracellluar"
 * "The functional target(s) of intracellular inhibitory serpins have been more challenging to elucidate than their extracellular counterparts." could be better as "In contrast, the targets of intracellular inhibitory serpins have been more difficult to identify."
 * Over-use of the word "can" makes prose appear indecisive, "antitrypsin deficiency can cause emphysema", if this phenotype has high penetrance, just say "antitrypsin deficiency causes emphysema"
 * As a general rule, try to avoid the passive, past tense. It can make even these fascinating proteins appear very dull!
 * eg - *"in order to inhibit" is better as "when they inhibit" or "as they bind proteases, these proteins undergo a dramatic..." active, present tense makes most things read clearer and better.
 * You never need to say "have been shown to do X" or "studies have shown that X" or "recent research has demonstrated that X" all these phrases do not make your meaning any clearer but only add superfluous and distracting words. Just say "they do X" or "X is"
 * "Serpins also possess an exposed region termed the reactive centre (or site) loop (RCL) that (for inhibitory molecules)" - Too many parentheses (by far)!
 * "concomittently" - we're writing for the general public, "at the same time" or "simultaneously" are more widely-understood words.
 * "PAI-1 is released in the native conformation, however, rapidly undergoes conformational change" - I don't think this says what you intended.

Have gone through, made all the changes requested above, and also edited to make the article more succinct. Jcwhizz 00:13, 4 August 2007 (UTC)


 * 2. Factually accurate?:
 * I've not come across "Archae" before, isn't Archaea the more usual term?

Sorry - spello. Jcwhizz 00:13, 4 August 2007 (UTC)


 * "These enzymes are defined by the presence of a serine residue in their catalytic site." Many, if not most enzymes contain at least one serine in their active site (which is where the link goes). It is the nucleophilic serine in the enzymatic reaction mechanism that defines this class.

Added the term nucleophilic to make this distinction for both serine and cysteine. Jcwhizz 00:13, 4 August 2007 (UTC)


 * "the lack of precise synteny between human serpins and the serpins of model organisms such as the mouse complicates functional characterisation." I don't understand this, if sequence similarity is high enough gene order is irrelevant, if order is conserved but sequence diverges,you can't assume shared functions. Surely sequence is more important than synteny?

Have replaced with functional orthology. Basically the problem is that the murine repotoire of serpins is vastly expanded with respect to human serpins. So for example, where there is one human gene for SCCA-1, there are 3-4 in the mouse. Thus it is difficult to know which one to knock out to gain an understanding of the role of the human protein. Jcwhizz 00:13, 4 August 2007 (UTC)


 * "cytotoxic granule protease granzyme B" is this an example of inappropriate intracellular activation of proteases? The way it follows this statement makes me suspect this, but the example doesn't explain enough for me to be sure.

Yes, in certain cases, for example in Tcell killing, there may be some "leakage" of Granzymes during granzyme delivery which are most likely mopped up by serpins such as PI-9. Have changed text to clarify this. Jcwhizz 00:13, 4 August 2007 (UTC)


 * I don't think allosteric modulators are often referred to as "cofactors", as this term is usually reserved for compounds required for an enzymatic activity. You could just say "binding of activators and inhibitors"

In this instance I think it is appropriate to - within the serpin field the term co-factor is generally accepted and used to describe molecules that modulate serpin inhibitory activity. See for example, Frank Church's recent review (Rau et al., J Thromb Haemost. 2007 Jul;5 Suppl 1:102-15) - but there many other papers on this topic. Jcwhizz 00:13, 4 August 2007 (UTC)


 * 3. Broad in coverage?:
 * Yes.


 * 4. Neutral point of view?:
 * A bit pro-serpin! :) but OK

Yes, I have to confess I have an interest :) Jcwhizz 00:13, 4 August 2007 (UTC)


 * 5. Article stability?
 * Not a concern.


 * 6. Images?:
 * The images are great, but the captions are a bit on the long side. Perhaps some of the text discussing the images, rather than just giving the components and colouring might be moved to the text?

Yes, good point - have shortened all legends, and moved the text of figure 4 (function of heparin) into the text. I have left the odd sentence to really emphasize key points. Jcwhizz 00:13, 4 August 2007 (UTC)

I've put this nomination on hold while the minor text changes are made. If you feel that this review is in error, feel free to take it to a GA review. Thank you to all of the editors who worked hard to bring it to this status. Tim Vickers 21:41, 31 July 2007 (UTC)

Thanks once again for a great and detailed review. Are you happy with the changes? Cheers James Jcwhizz 00:13, 4 August 2007 (UTC)


 * Very happy, congratulations it is a Good Article! Tim Vickers 14:13, 4 August 2007 (UTC)

Thanks Tim - excellent!! - I'll have a read on what is required for nomination for FA. Cheers James Jcwhizz 22:11, 4 August 2007 (UTC)


 * As a pointer for FA, the main areas to improve are the lack of a simple organisation, with structure and function interspersed, as well as the prose, which is still written for a specialist audience. I've always imagined FA science articles as aiming for Scientific American/New Scientist level of approachability. Perhaps the closest FA to this topic is the one on DNA, that might give some useful comparisons? Good luck and good writing! Tim Vickers 23:09, 4 August 2007 (UTC)

Problem with Figure 3
Figure 3, "Catalytic mechanism of serine proteases" - The reaction mechanism has some problems. The nitrogen in the carboxamide kinda disappears in the last couple steps and seems to maybe be replaced with an oxygen... —Preceding unsigned comment added by 65.67.67.220 (talk) 22:10, 8 November 2007 (UTC)

The cleaved product leaves the active site then water comes in to complete hydrolysis of the acyl enzyme intermediate. Not sure what problem you are refering to - looks like a pretty standard depiction of the reaction mechanism to me.

Jcwhizz 23:04, 9 November 2007 (UTC)


 * I made a modified version of the figure, is this any clearer? Tim Vickers 23:51, 9 November 2007 (UTC)

Hi - thats great!! Jcwhizz 08:37, 13 November 2007 (UTC)

I love this page. I added a short description of the uterine serpins with a link to a new page I wrote on them. I hope that is OK. If not, please delete or modify. Ufpete (talk) 12:06, 3 December 2010 (UTC)

Split to reduce size
Article is large and slow to format. It has over 170 references. Should we split it ? Would it be sensible to split out Table 1 (which alone has over 70 references) ? Rod57 (talk) 09:12, 20 April 2011 (UTC)

Hi - I would be strongly against splitting it or splitting out table 1- basically the page is designed to give a comprehensive and well referenced overview of the serpin superfamily - table 1 is valuable because it gives a quick at a glance insight into the human serpins, which are of primary interest from a medical research perspective. James Whisstock (talk) 12:06, 13 September 2011 (UTC)

How to move this to FA
In response to a previous question by Jcwhizz of how to move this article to FA. Here are my suggestions (some of which I shall try to implement myself over the coming weeks).

Content

 * The first section should probably be Activity and be about what they do i.e. inhibit proteases


 * Historical information scattered through the article and lead should be gathered into a single section
 * ✅ I've moved the current historical info into a single section. Will need some more key dates in there (e.g. First discovered serpin? First structure?)


 * Lead should only summarise info from elsewhere in the article (and ideally proportionately to the size of each section)
 * ✅ I've removed unique information down to various sections of the article and tried to include a sentence or two on each main section


 * The lead image should be the simplest to understand. From my limited knowledge, the PZI/PZ complex isn't the most common situation
 * ✅ I've made a new image for the lead that I hope includes the key points of a serpin


 * Several structure sections should be subsections under a general Structure section


 * Similarly, the pathology sections should be grouped under one heading


 * I'll actually semi-disagree with Tim Vickers here are suggest that the captions should describe the key point that the reader should understand from it (from the 2007 GA review)
 * E.g it's not immediately obvious what the significance of the current Fig.12 is just from its caption
 * I think it should still be possible to keep these succinct if a general audience is kept in mind
 * ✅ Tried to write short captions that highlight the specific point that the image is trying to convey.


 * The Types and Disease sections could both be shortened by 20-40% to retain balance with the rest of the article
 * ✅ Types section neatened and shortened by default collapse of megatable
 * ✅ I've rearranged the Disease section so that the simpler-to-understand mechanisms of disease are given first


 * There were 5 paragraphs and an image on the A-sheet model of polymerisation before it was then stated that it's thought to not be physiologically relevant.
 * ✅ I've removed it for now since it seems heavily over-weighted for a model that is no longer thought to be relevant. I think t that's reasonable given that this is not a historical review of overturned theories, but an encyclopedic summary of what is though to be the correct. I've saved the text below in case I'm missing something obvious though!



In the absence of definitive structural data, it was, therefore, postulated that serpins polymerise via a mechanism known as A-sheet polymerisation. In normal function the RCL inserts into the A β-sheet to form a fourth strand. In the A-sheet polymerisation model, it was suggested that the RCL of one serpin molecule spontaneously inserted into the A-sheet of another, to form a long-chain polymer (figure 9). In effect, it was, thus, proposed that polymerization occurred as a consequence of the requirement of the serpin scaffold to accept an additional β-strand.

Serpins were one of the first families for which disease-causing mutations were directly analyzed in reference to the available crystal structures. In support of the A-sheet polymerisation model, it was noted that many serpin mutations that cause polymerisation localise to two distinct regions of the molecule termed the shutter and the breach. The shutter and the breach contain highly conserved residues, underlie the path of RCL insertion, and are proposed to be important for conformational change.

Two structures of cleaved serpin polymers have been solved; both of which reveal RCL / A-sheet sheet linkages similar to those predicted by the A sheet polymerisation mechanism. However, in direct contrast to the known properties of physiological serpin polymers, crystals of cleaved serpin A-sheet polymers readily dissociate into monomeric forms.

Events associated with serpin polymerisation occur during the folding of the molecule, and that mutations that cause serpinopathies interfere with the ability of the serpin to fold to the metastable native state. In normal serpin folding, the serpin rapidly moves through a key folding intermediate to attain the native state. It is the serpin folding intermediate that has the ability to polymerise, hence it is important that this folding species rapidly moves on to adopt native state. Mutations such as the Z-antitrypsin variant (Glu 342 to Lys) somehow prevent the final stage of seprin folding and cause the accumulation of the folding intermediate. As a result, population of the folding intermediate resulted in polymer formation. It was noted that once folded, the Z-antitrypsin variant closely resembles wild-type material in terms of thermal stability and inhibitory activity.

Together, these data have presented an important challenge to the A-sheet model for serpin polymerisation. On the one hand, the idea that serpin polymer formation essentially takes advantage of the serpin mechanism of conformational change is an attractive one. On the other, the biophyiscal data in particular suggest that it is a folding intermediate (rather than the native form) that polymerises, and it is clear that this intermediate must have different structural properties to the native, folded state.

It is thought that physiological serpin polymers do not form via the A-sheet mechanism, but instead form via more extensive domain swapping events.

Style

 * The page still contains a lot of scientific review-isms
 * e.g. "It should additionally be noted that..." / "Early studies on serpins revealed that..." (removal doesn't change the sentence)
 * e.g. "Rawlings et al. showed that..." (The researcher is irrelevant in this sentence, and is amply covered by the reference)
 * ✅ Reworded most of the main review-style statements.


 * References to specific figures aren't really part of the style (since the number and order can change over time) and ideally the images stand alone anyway
 * ✅ I've gone through all of the cations to try to capture the key point being illustrated by the figure, whilst still retaining colour and PDB information.


 * I agree that the classification mega-table should stay, but we could use a collapsed table to ease readability of the rest of the page (like in the catalytic triad article)
 * ✅ and also a few formatting changes to it


 * The word serpin doesn't need to appear in the section headings


 * Terms like 'recently' make the page harder to keep up to date. Dates can be used, or the recentness can be omitted all together
 * ✅ Important dates could maybe be included in the History section


 * PDB codes should be auto-formatted by a template (more robust and easier to edit)
 * ✅ Have used template in figure legends and  in the table


 * PDB codes not in figure legends should probably be footnotes for the main text, since they're basically references
 * ✅ although there was actually only one occurrence in the end which later turned out to be redundant.


 * Images should ideally have white backgrounds and full-resolution version should be >1000px wide.
 * ✅ I've updated several of the key images early in the article.

Optional
With these changes, I think it'd be reasonable to submit it for FA nomination and see what the reviewers identify. Although it looks like a lot, I don't think it'll take too much to fix up these bits and pieces. T.Shafee(Evo&#65120;Evo)talk 11:27, 1 November 2015 (UTC)
 * Since the unique mechanism of these proteins is so visually striking, an animation would be ideal. However, this entirely depends on availability of something that can be put under a creative commons copyright license

Summary of changes (Nov-Dec 2015)
I've managed to do most of the big changes that I identified above ( and changes).

The main changes have been:
 * Rearrangement of the main headings to better group information
 * General language simplification
 * First sentences of all sections should be layman-understandable (hopefully)
 * Updates of images to better highlight key points
 * Removal of figure numbers and more descriptive captions

I've also taken the liberty of updating some of the images. Hopefully they're clearer. T.Shafee(Evo&#65120;Evo)talk 05:53, 20 December 2015 (UTC)

To be addressed by a serpin expert
1. When were the first serpins discovered, and when was the first structure solved?


 * The term serpin is generally accepted in the field to have been coined by Robin Carrell and Jim Travis in 1985 - however, proteins such as antitrypsin, antithrombin and ovalbumin have been known since the 19230's and probably earlier.  Indeed, the first report of the protease inhibitory activity in human plasma dates (to my knowledge) to 1894
 * Fermi C, Pernossi L. Untersuchungen uber die enzyme, Ver- gleichende Studie. Z Hyg Infektionskr 1894;18:83e9.
 * The relationship between different serpin family members became apparent in the early 1980's with this classic paper Biochem Biophys Res Commun. 1980 Jul 31;95(2):864-71.
 * A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor. Hunt LT, Dayhoff MO.
 * Also notable is the work of Doolittle - angiotensinogen being a strikingly diverged family member.
 * Angiotensinogen is related to the antitrypsin-antithrombin-ovalbumin family. Doolittle RF. Science. 1983 Oct 28;222(4622):417-9.


 * First crystal structures:
 * Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. Loebermann H, Tokuoka R, Deisenhofer J, Huber R. J Mol Biol. 1984 Aug 15;177(3):531-57.


 * Its interesting to note that this was the cleaved form of antitrypsin - there likely would not have been the initial interest in the family if the native form was determined first - the fact that the region supposed to interact with the target protease was buried was a huge surprise and suggested a major conformational change.


 * The next two structures were in the S state - one of cleaved plakalbumin - which does not undergo the S to R transition and then the first native serpin solved by Penny Stein - ovalbumin.


 * Crystal structure of plakalbumin, a proteolytically nicked form of ovalbumin. Its relationship to the structure of cleaved alpha-1-proteinase inhibitor. Wright HT, Qian HX, Huber R. J Mol Biol. 1990 Jun 5;213(3):513-28.


 * Crystal structure of ovalbumin as a model for the reactive centre of serpins. Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW Nature. 1990 Sep 6;347(6288):99-102.

2. Are most serpin-related diseases due to polymerisation or inactivity? From the information balance in the article, currently it looks as though pathologies due to merely inactive serpins are rare.


 * Most serpin-related disease are linked to polymerisation - however, since polymerisation results in an inactive serpin, many aspects of serpinopathies relate to loss of proper control of proteases - the classic being alpha one - liver disease caused by polymers in the ER, lung disease through failure to properly control elastase.

3. Are there any pathologies of over-active serpins?


 * None that I'm immediately aware of - I'll have a think though.

4. Is anything known about the evolution of non-inhibitory serpins? Does the RCL have an intersting role in any of them or are they just inert storage/ carrier proteins?


 * Absolutely - see the section of CBG and TBG - both bind hormones tightly in the stressed form and less tightly in the Relaxed conformation. Other non inhibitory sermons, for example, HSP47 seem to function just in the S state.

5. Is there anything interesting to be said about how the high-energy stressed state is produced by the ribosome? E.g. a sentence in the Structure section.


 * This question is complex and relates to folding mechanism. No ribosome studies have been done to my knowledge, however, from the perspective of how the S state folds, I like to think of it as a race between getting to native, and alternatively forming polymer.  I think latent is reached through native, although this is incompletely understood.

I'll add to the above list if I think of any more things! T.Shafee(Evo&#65120;Evo)talk 11:08, 13 December 2015 (UTC)


 * Responses by 09:36, 25 December 2015‎


 * Thanks for the answers . I've updated the article where appropriate to reflect them. T.Shafee(Evo&#65120;Evo)talk 03:09, 1 January 2016 (UTC)

Featured Article nomination

 * Discussion transcluded from Featured article candidates/Serpin/archive1

External links modified
Hello fellow Wikipedians,

I have just modified one external link on Serpin. Please take a moment to review my edit. If you have any questions, or need the bot to ignore the links, or the page altogether, please visit this simple FaQ for additional information. I made the following changes:
 * Added archive https://web.archive.org/web/20060504050207/http://pharm.kuleuven.be/biotech/index.htm to http://pharm.kuleuven.be/biotech/index.htm

When you have finished reviewing my changes, you may follow the instructions on the template below to fix any issues with the URLs.

Cheers.— InternetArchiveBot  (Report bug) 13:16, 24 September 2017 (UTC)