{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:51:11Z","timestamp":1791557471305,"version":"4.3.4"},"reference-count":103,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T00:00:00Z","timestamp":1676246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["22077010"],"award-info":[{"award-number":["22077010"]}]},{"name":"National Natural Science Foundation of China","award":["22277009"],"award-info":[{"award-number":["22277009"]}]},{"name":"National Natural Science Foundation of China","award":["2021YFC2103900"],"award-info":[{"award-number":["2021YFC2103900"]}]},{"name":"National Natural Science Foundation of China","award":["XK2022-07"],"award-info":[{"award-number":["XK2022-07"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["22077010"],"award-info":[{"award-number":["22077010"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["22277009"],"award-info":[{"award-number":["22277009"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["2021YFC2103900"],"award-info":[{"award-number":["2021YFC2103900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&amp;D Program of China","doi-asserted-by":"publisher","award":["XK2022-07"],"award-info":[{"award-number":["XK2022-07"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Joint Project of BRC-BC (Biomedical Translational Engineering Research Center of BUCT-CJFH)","award":["22077010"],"award-info":[{"award-number":["22077010"]}]},{"name":"Joint Project of BRC-BC (Biomedical Translational Engineering Research Center of BUCT-CJFH)","award":["22277009"],"award-info":[{"award-number":["22277009"]}]},{"name":"Joint Project of BRC-BC (Biomedical Translational Engineering Research Center of BUCT-CJFH)","award":["2021YFC2103900"],"award-info":[{"award-number":["2021YFC2103900"]}]},{"name":"Joint Project of BRC-BC (Biomedical Translational Engineering Research Center of BUCT-CJFH)","award":["XK2022-07"],"award-info":[{"award-number":["XK2022-07"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Transthyretin (TTR) aggregation and amyloid formation are associated with several ATTR diseases, such as senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP). However, the mechanism that triggers the initial pathologic aggregation process of TTR remains largely elusive. Lately, increasing evidence has suggested that many proteins associated with neurodegenerative diseases undergo liquid\u2013liquid phase separation (LLPS) and subsequent liquid-to-solid phase transition before the formation of amyloid fibrils. Here, we demonstrate that electrostatic interactions mediate LLPS of TTR, followed by a liquid-solid phase transition, and eventually the formation of amyloid fibrils under a mildly acidic pH in vitro. Furthermore, pathogenic mutations (V30M, R34T, and K35T) of TTR and heparin promote the process of phase transition and facilitate the formation of fibrillar aggregates. In addition, S-cysteinylation, which is a kind of post-translational modification of TTR, reduces the kinetic stability of TTR and increases the propensity for aggregation, while another modification, S-sulfonation, stabilizes the TTR tetramer and reduces the aggregation rate. Once TTR was S-cysteinylated or S-sulfonated, they dramatically underwent the process of phase transition, providing a foundation for post-translational modifications that could modulate TTR LLPS in the context of pathological interactions. These novel findings reveal molecular insights into the mechanism of TTR from initial LLPS and subsequent liquid-to-solid phase transition to amyloid fibrils, providing a new dimension for ATTR therapy.<\/jats:p>","DOI":"10.3390\/ijms24043729","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T04:32:58Z","timestamp":1676262778000},"page":"3729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Regulatory Mechanism of Transthyretin Irreversible Aggregation through Liquid-to-Solid Phase Transition"],"prefix":"10.3390","volume":"24","author":[{"given":"Guangfei","family":"Duan","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqin","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meimei","family":"Ye","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hexin","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhong","family":"Luo","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2015.09.015","article-title":"Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization","volume":"163","author":"Molliex","year":"2015","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.tcb.2018.02.004","article-title":"Protein Phase Separation: A New Phase in Cell Biology","volume":"28","author":"Boeynaems","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.cell.2015.07.047","article-title":"A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation","volume":"162","author":"Patel","year":"2015","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e98049","DOI":"10.15252\/embj.201798049","article-title":"Tau protein liquid\u2013liquid phase separation can initiate tau aggregation","volume":"37","author":"Wegmann","year":"2018","journal-title":"EMBO J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41594-018-0064-2","article-title":"Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation","volume":"25","author":"Guenther","year":"2018","journal-title":"Nat. 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