{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T16:23:31Z","timestamp":1788020611812,"version":"build-2784847793"},"reference-count":71,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T00:00:00Z","timestamp":1638489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-15-00123"],"award-info":[{"award-number":["21-15-00123"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-14-00289"],"award-info":[{"award-number":["19-14-00289"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>S100A1 is a member of the S100 family of small ubiquitous Ca2+-binding proteins, which participates in the regulation of cell differentiation, motility, and survival. It exists as homo- or heterodimers. S100A1 has also been shown to bind Zn2+, but the molecular mechanisms of this binding are not yet known. In this work, using ESI-MS and ITC, we demonstrate that S100A1 can coordinate 4 zinc ions per monomer, with two high affinity (KD~4 and 770 nm) and two low affinity sites. Using competitive binding experiments between Ca2+ and Zn2+ and QM\/MM molecular modeling we conclude that Zn2+ high affinity sites are located in the EF-hand motifs of S100A1. In addition, two lower affinity sites can bind Zn2+ even when the EF-hands are saturated by Ca2+, resulting in a 2Ca2+:S100A1:2Zn2+ conformer. Finally, we show that, in contrast to calcium, an excess of Zn2+ produces a destabilizing effect on S100A1 structure and leads to its aggregation. We also determined a higher affinity to Ca2+ (KD~0.16 and 24 \u03bcm) than was previously reported for S100A1, which would allow this protein to function as a Ca2+\/Zn2+-sensor both inside and outside cells, participating in diverse signaling pathways under normal and pathological conditions.<\/jats:p>","DOI":"10.3390\/biom11121823","type":"journal-article","created":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T20:59:33Z","timestamp":1638737973000},"page":"1823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mechanism of Zn2+ and Ca2+ Binding to Human S100A1"],"prefix":"10.3390","volume":"11","author":[{"given":"Viktoriia E.","family":"Baksheeva","sequence":"first","affiliation":[{"name":"Institut de Neurophysiopathologie, INP, CNRS, Facult\u00e9 des Sciences M\u00e9dicales et Param\u00e9dicales, Aix-Marseille Universit\u00e9, 13005 Marseille, France"},{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei Yu.","family":"Roman","sequence":"additional","affiliation":[{"name":"Institut de Neurophysiopathologie, INP, CNRS, Facult\u00e9 des Sciences M\u00e9dicales et Param\u00e9dicales, Aix-Marseille Universit\u00e9, 13005 Marseille, France"},{"name":"Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Villard","sequence":"additional","affiliation":[{"name":"Institut de Neurophysiopathologie, INP, CNRS, Facult\u00e9 des Sciences M\u00e9dicales et Param\u00e9dicales, Aix-Marseille Universit\u00e9, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5990-8898","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Devred","sequence":"additional","affiliation":[{"name":"Institut de Neurophysiopathologie, INP, CNRS, Facult\u00e9 des Sciences M\u00e9dicales et Param\u00e9dicales, Aix-Marseille Universit\u00e9, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Byrne","sequence":"additional","affiliation":[{"name":"Institut de Microbiologie de la M\u00e9diterran\u00e9e, CNRS, FR3479, Aix-Marseille Universit\u00e9, 13402 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahbia","family":"Yatoui","sequence":"additional","affiliation":[{"name":"Institut de Neurophysiopathologie, INP, CNRS, Facult\u00e9 des Sciences M\u00e9dicales et Param\u00e9dicales, Aix-Marseille Universit\u00e9, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6987-8119","authenticated-orcid":false,"given":"Arthur O.","family":"Zalevsky","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5550-2129","authenticated-orcid":false,"given":"Alisa A.","family":"Vologzhannikova","sequence":"additional","affiliation":[{"name":"Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey S.","family":"Sokolov","sequence":"additional","affiliation":[{"name":"Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4086-3137","authenticated-orcid":false,"given":"Sergei E.","family":"Permyakov","sequence":"additional","affiliation":[{"name":"Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-4268","authenticated-orcid":false,"given":"Andrey V.","family":"Golovin","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia"},{"name":"Sirius University of Science and Technology, 354340 Sochi, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4685-9625","authenticated-orcid":false,"given":"Gary S.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-8836","authenticated-orcid":false,"given":"Philipp O.","family":"Tsvetkov","sequence":"additional","affiliation":[{"name":"Institut de Neurophysiopathologie, INP, CNRS, Facult\u00e9 des Sciences M\u00e9dicales et Param\u00e9dicales, Aix-Marseille Universit\u00e9, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3013-7863","authenticated-orcid":false,"given":"Evgeni Yu.","family":"Zernii","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0167-4889(99)00058-0","article-title":"Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type","volume":"1450","author":"Donato","year":"1999","journal-title":"Biochim. 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