{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T03:50:42Z","timestamp":1762660242028,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"United Kingdom Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R016984\/1"],"award-info":[{"award-number":["MR\/R016984\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Research and University Dipartimenti di Eccellenza","award":["MR\/R016984\/1"],"award-info":[{"award-number":["MR\/R016984\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its aggregation propensity. The association between free calcium ions (Ca2+) and TTR is still debated, although recent work seems to suggest that calcium induces structural destabilization of TTR and promotes its aggregation at non-physiological low pH in vitro. We apply high-resolution NMR spectroscopy to investigate calcium binding to TTR showing the formation of labile interactions, which leave the native structure of TTR substantially unaltered. The effect of calcium binding on TTR-enhanced aggregation is also assessed at physiological pH through the mechano-enzymatic mechanism. Our results indicate that, even if the binding is weak, about 7% of TTR is likely to be Ca2+-bound in vivo and therefore more aggregation prone as we have shown that this interaction is able to increase the protein susceptibility to the proteolytic cleavage that leads to aggregation at physiological pH. These events, even if involving a minority of circulating TTR, may be relevant for ATTR, a pathology that takes several decades to develop.<\/jats:p>","DOI":"10.3390\/biom12081066","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T21:41:37Z","timestamp":1659476497000},"page":"1066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Calcium Binds to Transthyretin with Low Affinity"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3435-9807","authenticated-orcid":false,"given":"Cristina","family":"Cantarutti","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"},{"name":"Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Chiara","family":"Mimmi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guglielmo","family":"Verona","sequence":"additional","affiliation":[{"name":"Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Mandaliti","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham W.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. Patrizia","family":"Mangione","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy"},{"name":"Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Giorgetti","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy"},{"name":"Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittorio","family":"Bellotti","sequence":"additional","affiliation":[{"name":"Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy"},{"name":"Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK"},{"name":"Scientific Direction, Fondazione IRCCS Policlinico San Matteo, 27100 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, University of Udine, 33100 Udine, Italy"},{"name":"Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1073\/pnas.87.7.2843","article-title":"Fibril in Senile Systemic Amyloidosis Is Derived from Normal Transthyretin","volume":"87","author":"Westermark","year":"1990","journal-title":"Proc. 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