{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T01:58:50Z","timestamp":1782179930312,"version":"3.54.5"},"reference-count":48,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Molecular Recognition"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Systemic light\u2010chain amyloidosis (AL) is caused by the misfolding and aggregation of immunoglobulin light chains (LCs), which natively form homodimers comprising variable (VL) and constant (CL) domains in each monomer. High sequence variability, particularly within the VL domain, results in varied structural changes and aggregation propensities, making it challenging to develop broadly effective native protein stabilizers\/aggregation inhibitors, as each AL patient carries a unique light chain. Using artificial intelligence (AI)\u2010based AlphaFold2, known for its accuracy in modeling folded proteins, we generated an extensive repertoire of structural models of full\u2010length LCs from four amyloidogenic germlines: IGLV1(\u03bb1), IGLV3(\u03bb3), IGLV6(\u03bb6), and IGKV1(\u03ba1), over\u2010represented in AL patients to identify germline\u2010specific structural features. The resulting models cover multiple structural folds, benchmarked against the Protein Data Bank (PDB) deposited structures. We identified clear germline\u2010specific structural patterns: \u03bb6 and \u03bb1 LCs frequently adopt open dimers, with two VL domains far apart, in 86% and 72% of predicted structures, respectively. The open structures are under\u2010represented in the PDB due to the limited availability of structural data for each amyloidogenic germline. In contrast, \u03bb3 shows 48% open dimers, while \u03ba1 consistently forms closed dimers. These trends mirror clinical prevalence and aggregation propensity with an order of \u03bb6\u2009&gt;\u2009\u03bb1\u2009&gt;\u2009\u03bb3\u2009&gt;\u2009\u03ba1 in AL patients. Moreover, adopting open conformations, but not the number of mutations, correlates with a higher aggregation propensity in amyloidogenic germlines. This study identifies germline\u2010specific structural features as broadly applicable therapeutic targets, potentially reducing the cost and complexity of personalized treatments for polymorphic disease, AL amyloidosis.<\/jats:p>","DOI":"10.1002\/jmr.70011","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:58:51Z","timestamp":1756774731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Conformational Landscape of <scp>AlphaFold2<\/scp>\u2010Predicted Amyloidogenic Light Chains and Their Correlation With <scp>VL<\/scp> Domain Mutations and Aggregation Propensity"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0896-9460","authenticated-orcid":false,"given":"Sarita","family":"Puri","sequence":"first","affiliation":[{"name":"Biology Department Indian Institute of Science Education and Research  Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishaan","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Biology Department Indian Institute of Science Education and Research  Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnav","family":"Khatri","sequence":"additional","affiliation":[{"name":"Biology Department Indian Institute of Science Education and Research  Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basudha","family":"Patel","sequence":"additional","affiliation":[{"name":"Biology Department Indian Institute of Science Education and Research  Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Kumawat","sequence":"additional","affiliation":[{"name":"Department of Physics University of Cagliari  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharvari","family":"Palkar","sequence":"additional","affiliation":[{"name":"Biology Department Indian Institute of Science Education and Research  Pune India"},{"name":"Rajiv Gandhi Institute of IT and Biotechnology  Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9934-3043","authenticated-orcid":false,"given":"Gourab","family":"Das","sequence":"additional","affiliation":[{"name":"Bioinformatics &amp; Computational Biology Facility (BCBF), Advanced Centre for Treatment Research and Education in Cancer  Navi Mumbai Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1254-0023","authenticated-orcid":false,"given":"Prasanna","family":"Venkatraman","sequence":"additional","affiliation":[{"name":"Protein Interactome Lab for Structural and Functional Biology, Advanced Centre for Treatment Research and Education in Cancer  Navi Mumbai Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0034-3"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CC04396E"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.14797\/mdcvj.1070"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26684"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(94)90185-6"},{"key":"e_1_2_11_7_1","volume-title":"Immunobiology: The Immune System in Health and Disease","author":"Janeway C. A.","year":"2001"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005169"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-16953-7"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52300"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107174"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100334"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.08.021"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817538116"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.12.015"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2010.02.012"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-355784"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.3.714"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-743997"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-09-2707"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(89)90135-6"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817567116"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444902004183"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2025.168958"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16390"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.10.024"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.102002"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168837"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2023.168320"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/13506120802676781"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4067"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.445869"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0020514"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.2408420"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx670"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz758"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1012"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1039\/b706784b"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku399"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.062624507"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp691"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.051471205"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-93019-9"},{"key":"e_1_2_11_48_1","unstructured":"L.Schr\u00f6dingerandW.DeLano \u201cPyMOL \u201d(2020) http:\/\/www.pymol.org\/pymol."},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2023.2295221"}],"container-title":["Journal of Molecular Recognition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmr.70011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T02:32:05Z","timestamp":1758853925000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmr.70011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/jmr.70011"],"URL":"https:\/\/doi.org\/10.1002\/jmr.70011","archive":["Portico"],"relation":{},"ISSN":["0952-3499","1099-1352"],"issn-type":[{"value":"0952-3499","type":"print"},{"value":"1099-1352","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"2025-05-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70011"}}