The length scale of multivalent interactions is evolutionarily conserved in fungal and vertebrate phase-separating proteins
Abstract One key feature of proteins that form liquid droplets by phase separation inside a cell is multivalency—the presence of multiple sites that mediate interactions with other proteins. We know little about the variation of multivalency on evolutionary time scales. Here, we investigated the lon...
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One key feature of proteins that form liquid droplets by phase separation inside a cell is multivalency—the presence of multiple sites that mediate interactions with other proteins. We know little about the variation of multivalency on evolutionary time scales. Here, we investigated the long-term evolution (∼600 million years) of multivalency in fungal mRNA decapping subunit 2 protein (Dcp2), and in the FET (FUS, EWS and TAF15) protein family. We found that multivalency varies substantially among the orthologs of these proteins. However, evolution has maintained the length scale at which sequence motifs that enable protein–protein interactions occur. That is, the total number of such motifs per hundred amino acids is higher and less variable than expected by neutral evolution. To help explain this evolutionary conservation, we developed a conformation classifier using machine-learning algorithms. This classifier demonstrates that disordered segments in Dcp2 and FET proteins tend to adopt compact conformations, which is necessary for phase separation. Thus, the evolutionary conservation we detected may help proteins preserve the ability to undergo phase separation. Altogether, our study reveals that the length scale of multivalent interactions is an evolutionarily conserved feature of two classes of phase-separating proteins in fungi and vertebrates. |
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One key feature of proteins that form liquid droplets by phase separation inside a cell is multivalency—the presence of multiple sites that mediate interactions with other proteins. We know little about the variation of multivalency on evolutionary time scales. Here, we investigated the long-term evolution (∼600 million years) of multivalency in fungal mRNA decapping subunit 2 protein (Dcp2), and in the FET (FUS, EWS and TAF15) protein family. We found that multivalency varies substantially among the orthologs of these proteins. However, evolution has maintained the length scale at which sequence motifs that enable protein–protein interactions occur. That is, the total number of such motifs per hundred amino acids is higher and less variable than expected by neutral evolution. To help explain this evolutionary conservation, we developed a conformation classifier using machine-learning algorithms. This classifier demonstrates that disordered segments in Dcp2 and FET proteins tend to adopt compact conformations, which is necessary for phase separation. Thus, the evolutionary conservation we detected may help proteins preserve the ability to undergo phase separation. Altogether, our study reveals that the length scale of multivalent interactions is an evolutionarily conserved feature of two classes of phase-separating proteins in fungi and vertebrates.</description><identifier>ISSN: 1943-2631</identifier><identifier>ISSN: 0016-6731</identifier><identifier>EISSN: 1943-2631</identifier><identifier>DOI: 10.1093/genetics/iyab184</identifier><identifier>PMID: 34791214</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Algorithms ; Amino acid sequence ; Amino acids ; Animals ; Classifiers ; Communications ; Conservation ; Evolution ; Evolution, Molecular ; Evolutionary conservation ; Fungal Proteins - chemistry ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Fungi ; FUS protein ; Genetics ; Humans ; Machine learning ; mRNA ; Phase separation ; Protein interaction ; Proteins ; Vertebrates ; Vertebrates - genetics</subject><ispartof>Genetics (Austin), 2022-01, Vol.220 (1)</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c460t-3bdda49415b49f7c708377ca977412b70b34f660a5f52e549ea1356d2ceef8613</citedby><cites>FETCH-LOGICAL-c460t-3bdda49415b49f7c708377ca977412b70b34f660a5f52e549ea1356d2ceef8613</cites><orcidid>0000-0003-4299-3840 ; 0000-0002-4527-5302</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34791214$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Moses, A</contributor><creatorcontrib>Dasmeh, Pouria</creatorcontrib><creatorcontrib>Doronin, Roman</creatorcontrib><creatorcontrib>Wagner, Andreas</creatorcontrib><title>The length scale of multivalent interactions is evolutionarily conserved in fungal and vertebrate phase-separating proteins</title><title>Genetics (Austin)</title><addtitle>Genetics</addtitle><description>Abstract
One key feature of proteins that form liquid droplets by phase separation inside a cell is multivalency—the presence of multiple sites that mediate interactions with other proteins. We know little about the variation of multivalency on evolutionary time scales. Here, we investigated the long-term evolution (∼600 million years) of multivalency in fungal mRNA decapping subunit 2 protein (Dcp2), and in the FET (FUS, EWS and TAF15) protein family. We found that multivalency varies substantially among the orthologs of these proteins. However, evolution has maintained the length scale at which sequence motifs that enable protein–protein interactions occur. That is, the total number of such motifs per hundred amino acids is higher and less variable than expected by neutral evolution. To help explain this evolutionary conservation, we developed a conformation classifier using machine-learning algorithms. This classifier demonstrates that disordered segments in Dcp2 and FET proteins tend to adopt compact conformations, which is necessary for phase separation. Thus, the evolutionary conservation we detected may help proteins preserve the ability to undergo phase separation. Altogether, our study reveals that the length scale of multivalent interactions is an evolutionarily conserved feature of two classes of phase-separating proteins in fungi and vertebrates.</description><subject>Algorithms</subject><subject>Amino acid sequence</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Classifiers</subject><subject>Communications</subject><subject>Conservation</subject><subject>Evolution</subject><subject>Evolution, Molecular</subject><subject>Evolutionary conservation</subject><subject>Fungal Proteins - chemistry</subject><subject>Fungal Proteins - genetics</subject><subject>Fungal Proteins - metabolism</subject><subject>Fungi</subject><subject>FUS protein</subject><subject>Genetics</subject><subject>Humans</subject><subject>Machine learning</subject><subject>mRNA</subject><subject>Phase separation</subject><subject>Protein interaction</subject><subject>Proteins</subject><subject>Vertebrates</subject><subject>Vertebrates - genetics</subject><issn>1943-2631</issn><issn>0016-6731</issn><issn>1943-2631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1rHSEYhYfS0nx131URuimESXTUcdwUSuhHINBNshbHeWeuwatTdQYu_fP1cm9C2k1XevR5Dx5PVb0n-IpgSa8n8JCtSdd2p3vSsVfVKZGM1k1LyesX-5PqLKVHjHErefe2OqFMSNIQdlr9vt8AcuCnvEHJaAcojGi7uGzXInxG1meI2mQbfEI2IViDW_ZKR-t2yJRjiCsMBUTj4iftkPYDWiFm6KPOgOaNTlAnmHWR1k9ojiGD9emiejNql-DdcT2vHr59vb_5Ud_9_H578-WuNqzFuab9MGgmGeE9k6MwAndUCKOlEIw0vcA9ZWPbYs1H3gBnEjShvB0aAzB2LaHn1eeD77z0WxhMiRW1U3O0Wx13Kmir_r7xdqOmsKpOUMo4LQafjgYx_FogZbW1yYBz2kNYkmq4lOVrKdmjH_9BH8MSfYmnShEd5x3FolD4QJkYUoowPj-GYLVvVj01q47NlpEPL0M8DzxVWYDLAxCW-f92fwDKerVX</recordid><startdate>20220104</startdate><enddate>20220104</enddate><creator>Dasmeh, Pouria</creator><creator>Doronin, Roman</creator><creator>Wagner, Andreas</creator><general>Oxford University Press</general><general>Genetics Society of America</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>4T-</scope><scope>4U-</scope><scope>7QP</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4299-3840</orcidid><orcidid>https://orcid.org/0000-0002-4527-5302</orcidid></search><sort><creationdate>20220104</creationdate><title>The length scale of multivalent interactions is evolutionarily conserved in fungal and vertebrate phase-separating proteins</title><author>Dasmeh, Pouria ; Doronin, Roman ; Wagner, Andreas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c460t-3bdda49415b49f7c708377ca977412b70b34f660a5f52e549ea1356d2ceef8613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Algorithms</topic><topic>Amino acid sequence</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Classifiers</topic><topic>Communications</topic><topic>Conservation</topic><topic>Evolution</topic><topic>Evolution, Molecular</topic><topic>Evolutionary conservation</topic><topic>Fungal Proteins - chemistry</topic><topic>Fungal Proteins - genetics</topic><topic>Fungal Proteins - metabolism</topic><topic>Fungi</topic><topic>FUS protein</topic><topic>Genetics</topic><topic>Humans</topic><topic>Machine learning</topic><topic>mRNA</topic><topic>Phase separation</topic><topic>Protein interaction</topic><topic>Proteins</topic><topic>Vertebrates</topic><topic>Vertebrates - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dasmeh, Pouria</creatorcontrib><creatorcontrib>Doronin, Roman</creatorcontrib><creatorcontrib>Wagner, Andreas</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Docstoc</collection><collection>University Readers</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genetics (Austin)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dasmeh, Pouria</au><au>Doronin, Roman</au><au>Wagner, Andreas</au><au>Moses, A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The length scale of multivalent interactions is evolutionarily conserved in fungal and vertebrate phase-separating proteins</atitle><jtitle>Genetics (Austin)</jtitle><addtitle>Genetics</addtitle><date>2022-01-04</date><risdate>2022</risdate><volume>220</volume><issue>1</issue><issn>1943-2631</issn><issn>0016-6731</issn><eissn>1943-2631</eissn><abstract>Abstract
One key feature of proteins that form liquid droplets by phase separation inside a cell is multivalency—the presence of multiple sites that mediate interactions with other proteins. We know little about the variation of multivalency on evolutionary time scales. Here, we investigated the long-term evolution (∼600 million years) of multivalency in fungal mRNA decapping subunit 2 protein (Dcp2), and in the FET (FUS, EWS and TAF15) protein family. We found that multivalency varies substantially among the orthologs of these proteins. However, evolution has maintained the length scale at which sequence motifs that enable protein–protein interactions occur. That is, the total number of such motifs per hundred amino acids is higher and less variable than expected by neutral evolution. To help explain this evolutionary conservation, we developed a conformation classifier using machine-learning algorithms. This classifier demonstrates that disordered segments in Dcp2 and FET proteins tend to adopt compact conformations, which is necessary for phase separation. Thus, the evolutionary conservation we detected may help proteins preserve the ability to undergo phase separation. Altogether, our study reveals that the length scale of multivalent interactions is an evolutionarily conserved feature of two classes of phase-separating proteins in fungi and vertebrates.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>34791214</pmid><doi>10.1093/genetics/iyab184</doi><orcidid>https://orcid.org/0000-0003-4299-3840</orcidid><orcidid>https://orcid.org/0000-0002-4527-5302</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Algorithms Amino acid sequence Amino acids Animals Classifiers Communications Conservation Evolution Evolution, Molecular Evolutionary conservation Fungal Proteins - chemistry Fungal Proteins - genetics Fungal Proteins - metabolism Fungi FUS protein Genetics Humans Machine learning mRNA Phase separation Protein interaction Proteins Vertebrates Vertebrates - genetics |
title | The length scale of multivalent interactions is evolutionarily conserved in fungal and vertebrate phase-separating proteins |
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