{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:16:36Z","timestamp":1778562996510,"version":"3.51.4"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/OFIRG\/0007\/2016"],"award-info":[{"award-number":["NMRC\/OFIRG\/0007\/2016"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001459","name":"Ministry of Education -Singapore","doi-asserted-by":"crossref","award":["MOE2019-T2-1-138"],"award-info":[{"award-number":["MOE2019-T2-1-138"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Intrinsically disordered regions (IDRs) are prevalent in the eukaryotic proteome. Common functional roles of IDRs include forming flexible linkers or undergoing allosteric folding-upon-binding. Recent studies have suggested an additional functional role for IDRs: generating steric pressure on the plasma membrane during endocytosis, via molecular crowding. However, in order to accomplish useful functions, such crowding needs to be regulated in space (e.g., endocytic hotspots) and time (e.g., during vesicle formation). In this work, we explore binding-induced regulation of IDR steric volume. We simulate the IDRs of two proteins from Clathrin-mediated endocytosis (CME) to see if their conformational spaces are regulated via binding-induced expansion. Using Monte-Carlo computational modeling of excluded volumes, we generate large conformational ensembles (3 million) for the IDRs of Epsin and Eps15 and dock the conformers to the alpha subunit of Adaptor Protein 2 (AP2\u03b1), their CME binding partner. Our results show that as more molecules of AP2\u03b1 are bound, the Epsin-derived ensemble shows a significant increase in global dimensions, measured as the radius of Gyration (R<jats:sub>G<\/jats:sub>) and the end-to-end distance (EED). Unlike Epsin, Eps15-derived conformers that permit AP2\u03b1 binding at one motif were found to be more likely to accommodate binding of AP2\u03b1 at other motifs, suggesting a tendency toward co-accessibility of binding motifs. Co-accessibility was not observed for any pair of binding motifs in Epsin. Thus, we speculate that the disordered regions of Epsin and Eps15 perform different roles during CME, with accessibility in Eps15 allowing it to act as a recruiter of AP2\u03b1 molecules, while binding-induced expansion of the Epsin disordered region could impose steric pressure and remodel the plasma membrane during vesicle formation.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008474","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T19:30:01Z","timestamp":1609961401000},"page":"e1008474","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Computational modeling suggests binding-induced expansion of Epsin disordered regions upon association with AP2"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1857-8789","authenticated-orcid":true,"given":"N. Suhas","family":"Jagannathan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher W. V.","family":"Hogue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1301-7069","authenticated-orcid":true,"given":"Lisa","family":"Tucker-Kellogg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,1,6]]},"reference":[{"issue":"8","key":"pcbi.1008474.ref001","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm3151","article-title":"Molecular mechanism and physiological functions of clathrin-mediated endocytosis","volume":"12","author":"HT McMahon","year":"2011","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"5","key":"pcbi.1008474.ref002","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nrm.2017.132","article-title":"Mechanisms of clathrin-mediated endocytosis","volume":"19","author":"M Kaksonen","year":"2018","journal-title":"Nat Rev Mol Cell 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Carbone","year":"1997","journal-title":"Cancer Res"},{"issue":"1","key":"pcbi.1008474.ref026","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.sbi.2008.12.004","article-title":"Biophysical characterization of intrinsically disordered proteins","volume":"19","author":"D Eliezer","year":"2009","journal-title":"Current Opinion in Structural Biology"},{"key":"pcbi.1008474.ref027","first-page":"179","volume-title":"Methods in Enzymology","author":"ACM Ferreon","year":"2010"},{"issue":"94","key":"pcbi.1008474.ref028","article-title":"Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins","author":"S Bhattacharya","year":"2019","journal-title":"Biomolecules"},{"key":"pcbi.1008474.ref029","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.sbi.2017.01.006","article-title":"Computational and theoretical advances in studies of intrinsically disordered proteins","volume":"42","author":"RB Best","year":"2017","journal-title":"Curr 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