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- Title
Mechanism of Zn 2+ and Ca 2+ Binding to Human S100A1.
- Authors
Baksheeva, Viktoriia E.; Roman, Andrei Yu.; Villard, Claude; Devred, François; Byrne, Deborah; Yatoui, Dahbia; Zalevsky, Arthur O.; Vologzhannikova, Alisa A.; Sokolov, Andrey S.; Permyakov, Sergei E.; Golovin, Andrey V.; Shaw, Gary S.; Tsvetkov, Philipp O.; Zernii, Evgeni Yu.
- Abstract
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 μm) 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.
- Subjects
ZINC ions; CELL differentiation; CELLULAR control mechanisms; CELLULAR signal transduction; MONOMERS; CALCIUM ions
- Publication
Biomolecules (2218-273X), 2021, Vol 11, Issue 12, p1823
- ISSN
2218-273X
- Publication type
Article
- DOI
10.3390/biom11121823