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Mechanism of Zn 2+ and Ca 2+ Binding to Human S100A1

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.
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Contributor : François Devred Connect in order to contact the contributor
Submitted on : Friday, December 3, 2021 - 12:31:01 PM
Last modification on : Sunday, June 26, 2022 - 3:22:49 AM
Long-term archiving on: : Friday, March 4, 2022 - 7:00:36 PM


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Viktoriia E Baksheeva, Andrei Yu Roman, Claude Villard, François Devred, Deborah Byrne, et al.. Mechanism of Zn 2+ and Ca 2+ Binding to Human S100A1. Biomolecules, MDPI, 2021, 11 (12), pp.1823. ⟨10.3390/biom11121823⟩. ⟨hal-03464582⟩



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