{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T16:57:19Z","timestamp":1763139439698,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swedish Medical Research Council"},{"name":"Gerald Kerkutt Trust"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The calcium-binding protein S100A9 is recognized as an important component of the brain neuroinflammatory response to the onset and development of neurodegenerative disease. S100A9 is intrinsically amyloidogenic and in vivo co-aggregates with amyloid-\u03b2 peptide and \u03b1-synuclein in Alzheimer\u2019s and Parkinson\u2019s diseases, respectively. It is widely accepted that calcium dyshomeostasis plays an important role in the onset and development of these diseases, and studies have shown that elevated levels of calcium limit the potential for S100A9 to adopt a fibrillar structure. The exact mechanism by which calcium exerts its influence on the aggregation process remains unclear. Here we demonstrate that despite S100A9 exhibiting \u03b1-helical secondary structure in the absence of calcium, the protein exhibits significant plasticity with interconversion between different conformational states occurring on the micro- to milli-second timescale. This plasticity allows the population of conformational states that favour the onset of fibril formation. Magic-angle spinning solid-state NMR studies of the resulting S100A9 fibrils reveal that the S100A9 adopts a single structurally well-defined rigid fibrillar core surrounded by a shell of approximately 15\u201320 mobile residues, a structure that persists even when fibrils are produced in the presence of calcium ions. These studies highlight how the dysregulation of metal ion concentrations can influence the conformational equilibria of this important neuroinflammatory protein to influence the rate and nature of the amyloid deposits formed.<\/jats:p>","DOI":"10.3390\/ijms241713200","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T08:25:33Z","timestamp":1692951933000},"page":"13200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Stabilization of S100A9 Structure by Calcium Inhibits the Formation of Amyloid Fibrils"],"prefix":"10.3390","volume":"24","author":[{"given":"Ella","family":"Sanders","sequence":"first","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-8656","authenticated-orcid":false,"given":"Rebecca","family":"Csondor","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6925-4469","authenticated-orcid":false,"given":"Darius","family":"\u0160ulskis","sequence":"additional","affiliation":[{"name":"Sector of Amyloid Research, Institute of Biotechnology, Life Sciences Centre, Vilnius University, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5515-8528","authenticated-orcid":false,"given":"Ieva","family":"Baronait\u0117","sequence":"additional","affiliation":[{"name":"Sector of Amyloid Research, Institute of Biotechnology, Life Sciences Centre, Vilnius University, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1829-5455","authenticated-orcid":false,"given":"Vytautas","family":"Smirnovas","sequence":"additional","affiliation":[{"name":"Sector of Amyloid Research, Institute of Biotechnology, Life Sciences Centre, Vilnius University, LT-10257 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luckshi","family":"Maheswaran","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack","family":"Horrocks","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rory","family":"Munro","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5331-1978","authenticated-orcid":false,"given":"Christina","family":"Georgiadou","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-1430","authenticated-orcid":false,"given":"Istvan","family":"Horvath","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, Ume\u00e5 University, SE-90187 Ume\u00e5, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-2023","authenticated-orcid":false,"given":"Ludmilla A.","family":"Morozova-Roche","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, Ume\u00e5 University, SE-90187 Ume\u00e5, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0231-8640","authenticated-orcid":false,"given":"Philip T. F.","family":"Williamson","sequence":"additional","affiliation":[{"name":"Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"Kinney","year":"2018","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pajares, M., Rojo, A.I., Manda, G., Bosc\u00e1, L., and Cuadrado, A. (2020). Inflammation in Parkinson\u2019s Disease: Mechanisms and Therapeutic Implications. 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