{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T20:18:36Z","timestamp":1769285916008,"version":"3.49.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013868","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000}}],"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Partnership on Metrology, cofinanced from the European Union\u2019s Horizon Europe Research and Innovation Programme, and by the Participating States","award":["10.13039\/100019599"],"award-info":[{"award-number":["10.13039\/100019599"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>We present a novel method for analyzing the folding of intrinsically disordered proteins (IDPs), such as Tau and phosphorylated Tau (pTau), in solution. Using cross-linking mass spectrometry (XL-MS) combined with a new downstream analysis framework, we construct weighted interaction networks from cross-link\u2013derived residue pairs without relying on predefined secondary structure assumptions. Structural differences between protein conformations are quantified by comparing the organization of loop structures within their cross-link networks. Validation with bovine serum albumin (BSA) in native and denatured states shows that at least 500 cross-links\u2014requiring 5\u201310 replicate measurements\u2014are needed for reliable detection of structural divergence. Leave-one-out analysis confirms that structural transitions are global, highlighting the importance of comprehensive cross-link datasets. The coverage of unique cross-links was evaluated using accumulation curves from randomized permutations. Saturation levels were found to be 9.7%, 5.0%, and 6.2% of the total 528 and 10,731 possible cross-links after 30, 84, and 62 technical replicates, respectively, for myoglobin, native BSA, and denatured BSA. For Tau and pTau, coverage reached 10.8% and 5.5% of the upper limit (8,256). Finally, applying our structural analysis to Tau and pTau during arachidonic acid\u2013induced aggregation revealed distinct patterns of structural evolution between the two proteins.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013868","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T18:33:47Z","timestamp":1768415627000},"page":"e1013868","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cross-linking mass spectrometry for structure analysis of the intrinsically disordered Tau and phosphorylated Tau protein"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9963-5027","authenticated-orcid":true,"given":"Cristian","family":"Arsene","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0099-7480","authenticated-orcid":true,"given":"Alexander","family":"Gates","sequence":"additional","affiliation":[]},{"given":"Anne-Katrin","family":"R\u00f6mmert","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8243-3285","authenticated-orcid":true,"given":"Andr\u00e9","family":"M\u00e4rtens","sequence":"additional","affiliation":[]},{"given":"Valentina","family":"Faustinelli","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0643-8153","authenticated-orcid":true,"given":"Luise","family":"Luckau","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7812-6717","authenticated-orcid":true,"given":"Gavin","family":"O\u2019Connor","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"issue":"8","key":"pcbi.1013868.ref001","doi-asserted-by":"crossref","first-page":"7500","DOI":"10.1021\/acs.chemrev.1c00786","article-title":"Cross-linking mass spectrometry for investigating protein conformations and protein-protein interactions-a method for all seasons","volume":"122","author":"L Piersimoni","year":"2022","journal-title":"Chem Rev."},{"key":"pcbi.1013868.ref002","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.brainresbull.2016.08.018","article-title":"Tau and tauopathies","volume":"126","author":"T Arendt","year":"2016","journal-title":"Brain Res Bull."},{"issue":"33","key":"pcbi.1013868.ref003","doi-asserted-by":"crossref","first-page":"11442","DOI":"10.1021\/acs.analchem.1c01317","article-title":"Cross-linking\/mass spectrometry combined with ion mobility on a timsTOF pro instrument for structural proteomics","volume":"93","author":"CH Ihling","year":"2021","journal-title":"Anal Chem."},{"issue":"11","key":"pcbi.1013868.ref004","doi-asserted-by":"crossref","first-page":"6953","DOI":"10.1021\/acs.analchem.9b00658","article-title":"First community-wide, comparative cross-linking mass spectrometry study","volume":"91","author":"C Iacobucci","year":"2019","journal-title":"Anal Chem."},{"issue":"5","key":"pcbi.1013868.ref005","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1006\/jmbi.1998.1993","article-title":"Method for prediction of protein function from sequence using the sequence-to-structure-to-function paradigm with application to glutaredoxins\/thioredoxins and T1 ribonucleases","volume":"281","author":"JS Fetrow","year":"1998","journal-title":"J Mol Biol."},{"issue":"3","key":"pcbi.1013868.ref006","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0022-2836(80)90373-3","article-title":"How different amino acid sequences determine similar protein structures: the structure and evolutionary dynamics of the globins","volume":"136","author":"AM Lesk","year":"1980","journal-title":"J Mol Biol."},{"key":"pcbi.1013868.ref007","unstructured":"Schr\u00f6dinger LLC. 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