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Toward an understanding of the conformational plasticity of S100A8 and S100A9 Ca2+-binding proteins

Polakowska, Magdalena and Steczkiewicz, Kamil and Szczepanowski, Roman H. and Wysłouch-Cieszyńska, Aleksandra (2023) Toward an understanding of the conformational plasticity of S100A8 and S100A9 Ca2+-binding proteins. Journal of Biological Chemistry, 299 (4). p. 102952.


Official URL: https://www.jbc.org/article/S0021-9258(23)00084-4/...


S100A8 and S100A9 are small, human, Ca2+-binding proteins with multiple intracellular and extracellular functions in signaling, regulation, and defense. The two proteins are not detected as monomers but form various noncovalent homo- or hetero-oligomers related to specific activities in human physiology. Because of their significant roles in numerous medical conditions, there has been intense research on the conformational properties of various S100A8 and S100A9 proteoforms as essential targets of drug discovery. NMR or crystal structures are currently available only for mutated or truncated protein complexes, mainly with bound metal ions, that may well reflect the proteins' properties outside cells but not in other biological contexts in which they perform. Here, we used structural mass spectrometry methods combined with molecular dynamics simulations to compare the conformations of wildtype full-length S100A8 and S100A9 subunits in biologically relevant homo- and heterodimers and in higher oligomers formed in the presence of calcium or zinc ions. We provide, first, rationales for their functional response to changing environmental conditions, by elucidating differences between proteoforms in flexible protein regions that may provide the plasticity of the binding sites for the multiple targets, and second, the key factors contributing to the variable stability of the oligomers. The described methods and a systematic view of the conformational properties of S100A8 and S100A9 complexes provide a basis for further research to characterize and modulate their functions for basic science and therapies.

Item Type:Article
Subjects:Q Science > QD Chemistry
Divisions:Mass Spectrometry Laboratory
ID Code:2263
Deposited By: MSc Magdalena Polakowska
Deposited On:28 Apr 2023 11:00
Last Modified:28 Apr 2023 11:00

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