{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:48:32Z","timestamp":1776919712683,"version":"3.51.2"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","award":["2021\u201067456913"],"award-info":[{"award-number":["2021\u201067456913"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2022\u20100535"],"award-info":[{"award-number":["2022\u20100535"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The mechanism that converts native human transthyretin into amyloid fibrils <jats:italic>in vivo<\/jats:italic> is still a debated and controversial issue. Commonly, non\u2010physiological conditions of pH, temperature, or organic solvents are used in <jats:italic>in vitro<\/jats:italic> models of fibrillogenesis of globular proteins. Transthyretin amyloid formation can be achieved under physiological conditions through a mechano\u2010enzymatic mechanism involving specific serine proteases such as trypsin or plasmin. Here, we investigate S52P and L111M transthyretin variants, both causing a severe form of systemic amyloidosis mostly targeting the heart at a relatively young age with heterogeneous phenotype among patients. Our studies on thermodynamics show that both proteins are significantly less stable than other amyloidogenic variants. However, despite a similar thermodynamic stability, L111M variant seems to have enhanced susceptibility to cleavage and a lower tendency to form fibrils than S52P in the presence of specific proteases and biomechanical forces. Heparin strongly enhances the fibrillogenic capacity of L111M transthyretin, but has no effect on the S52P variant. Fibrillar seeds similarly affect the fibrillogenesis of both proteins, with a stronger effect on the L111M variant. According to our model of mechano\u2010enzymatic fibrillogenesis, both full\u2010length and truncated monomers, released after the first cleavage, can enter into fibrillogenesis or degradation pathways. Our findings show that the kinetics of the two processes can be affected by several factors, such as intrinsic amyloidogenicity due to the specific mutations, environmental factors including heparin and fibrillar seeds that significantly accelerate the fibrillogenic pathway.<\/jats:p>","DOI":"10.1002\/pro.4931","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T12:26:16Z","timestamp":1708518376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Degradation versus fibrillogenesis, two alternative pathways modulated by seeds and glycosaminoglycans"],"prefix":"10.1002","volume":"33","author":[{"given":"Guglielmo","family":"Verona","sequence":"first","affiliation":[{"name":"Centre for Amyloidosis University College London  London UK"},{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Raimondi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Canetti","sequence":"additional","affiliation":[{"name":"Centre for Amyloidosis University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. Patrizia","family":"Mangione","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"},{"name":"Research Department Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loredana","family":"Marchese","sequence":"additional","affiliation":[{"name":"Pathology Unit Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-1928","authenticated-orcid":false,"given":"Alessandra","family":"Corazza","sequence":"additional","affiliation":[{"name":"Department of Medicine (DAME) University of Udine  Udine Italy"},{"name":"Istituto Nazionale Biostrutture e Biosistemi  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Lavatelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia 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