{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:42:30Z","timestamp":1773412950816,"version":"3.50.1"},"reference-count":74,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/QUI\/00313\/2020"],"award-info":[{"award-number":["UIDB\/QUI\/00313\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/QUI\/00313\/2020"],"award-info":[{"award-number":["UIDP\/QUI\/00313\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>One of the molecular hallmarks of amyloidoses is ordered protein aggregation involving the initial formation of soluble protein oligomers that eventually grow into insoluble fibrils. The identification and characterization of molecular species critical for amyloid fibril formation and disease development have been the focus of intense analysis in the literature. Here, using photo-induced cross-linking of unmodified proteins (PICUP), we studied the early stages of oligomerization of human transthyretin (TTR), a plasma protein involved in amyloid diseases (ATTR amyloidosis) with multiple clinical manifestations. Upon comparison, the oligomerization processes of wild-type TTR (TTRwt) and several TTR variants (TTRV30M, TTRL55P, and TTRT119M) clearly show distinct oligomerization kinetics for the amyloidogenic variants but a similar oligomerization mechanism. The oligomerization kinetics of the TTR amyloidogenic variants under analysis showed a good correlation with their amyloidogenic potential, with the most amyloidogenic variants aggregating faster (TTRL55P &gt; TTRV30M &gt; TTRwt). Moreover, the early stage oligomerization mechanism for these variants involves stepwise addition of monomeric units to the growing oligomer. A completely different behavior was observed for the nonamyloidogenic TTRT119M variant, which does not form oligomers in the same acidic conditions and even for longer incubation times. Thorough characterization of the initial steps of TTR oligomerization is critical for better understanding the origin of ATTR cytotoxicity and developing novel therapeutic strategies for the treatment of ATTR amyloidosis.<\/jats:p>","DOI":"10.3390\/molecules25235698","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T20:09:40Z","timestamp":1607026180000},"page":"5698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Oligomerization Profile of Human Transthyretin Variants with Distinct Amyloidogenicity"],"prefix":"10.3390","volume":"25","author":[{"given":"Ana","family":"Frangolho","sequence":"first","affiliation":[{"name":"Chemistry Department and Coimbra Chemistry Centre, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"International Iberian Nanotechnology Laboratory, 4715-330 Braga, Portugal"}]},{"given":"Bruno E.","family":"Correia","sequence":"additional","affiliation":[{"name":"Chemistry Department and Coimbra Chemistry Centre, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"\u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne, CH-1015 Lausanne, Switzerland"}]},{"given":"Daniela C.","family":"Vaz","sequence":"additional","affiliation":[{"name":"Chemistry Department and Coimbra Chemistry Centre, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"CiTechCare, Center for Innovative Care and Health Technology, School of Health Sciences, Polytechnic Institute of Leiria, 2411-901 Leiria, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4097-2766","authenticated-orcid":false,"given":"Zaida L.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Chemistry Department and Coimbra Chemistry Centre, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9128-2557","authenticated-orcid":false,"given":"Rui M. M.","family":"Brito","sequence":"additional","affiliation":[{"name":"Chemistry Department and Coimbra Chemistry Centre, University of Coimbra, 3004-535 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,3]]},"reference":[{"key":"ref_1","first-page":"349","article-title":"Amyloid Formation by Transthyretin: From Protein Stability to Protein Aggregation","volume":"3","author":"Brito","year":"2003","journal-title":"Curr. Med. Chem. Endocr. Metab. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11793","DOI":"10.1016\/S0021-9258(17)39100-7","article-title":"Demonstration of transthyretin mRNA in the brain and other extrahepatic tissues in the rat","volume":"260","author":"Soprano","year":"1985","journal-title":"J. Biol. 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