Molecular Basis of S100A1 Activation and Target Regulation Within Physiological Cytosolic Ca Levels. Journal Article

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Authors: Sun, B; Kekenes-Huskey, PM
Article Title: Molecular Basis of S100A1 Activation and Target Regulation Within Physiological Cytosolic Ca Levels.
Abstract: The S100A1 protein regulates cardiomyocyte function through its binding of calcium (Ca) and target proteins, including titin, SERCA, and RyR. S100A1 presents two Ca binding domains, a high-affinity canonical EF-hand (cEF) and a low-affinity pseudo EF-hand (pEF), that control S100A1 activation. For wild-type S100A1, both EF hands must be bound by Ca to form the open state necessary for target peptide binding, which requires unphysiological high sub-millimolar Ca levels. However, there is evidence that post-translational modifications at Cys85 may facilitate the formation of the open state at sub-saturating Ca concentrations. Hence, post-translational modifications of S100A1 could potentially increase the Ca-sensitivity of binding protein targets, and thereby modulate corresponding signaling pathways. In this study, we examine the mechanism of S100A1 open-closed gating via molecular dynamics simulations to determine the extent to which Cys85 functionalization, namely via redox reactions, controls the relative population of open states at sub-saturating Ca and capacity to bind peptides. We further characterize the protein's ability to bind a representative peptide target, TRKT12 and relate this propensity to published competition assay data. Our simulation results indicate that functionalization of Cys85 may stabilize the S100A1 open state at physiological, micromolar Ca levels. Our conclusions support growing evidence that S100A1 serves as a signaling hub linking Ca and redox signaling pathways.
Journal Title: Frontiers in molecular biosciences
Publisher: Unknown  
Date Published: 2020