Abstract
The S100A1 protein regulates cardiomyocyte function through its binding of calcium (Ca2+) and target proteins, including titin, SERCA, and RyR. S100A1 presents two Ca2+ 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 Ca2+ to form the open state necessary for target peptide binding, which requires unphysiological high sub-millimolar Ca2+ levels. However, there is evidence that post-translational modifications at Cys85 may facilitate the formation of the open state at sub-saturating Ca2+ concentrations. Hence, post-translational modifications of S100A1 could potentially increase the Ca2+-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 Ca2+ 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 Ca2+ levels. Our conclusions support growing evidence that S100A1 serves as a signaling hub linking Ca2+ and redox signaling pathways.
Highlights
S100A1 is a Ca2+ binding protein that is implicated in cardiac and neurological functions (Wright et al, 2009b)
We introduced glutamic acid (E) or arginine (R) at site cysteine at the 85th position (C85) to approximate the effects of post-translational modifications including glutathionylation that modulate Ca2+ affinity (Goch et al, 2005)
We performed two extra simulations of S100A1 in the apo state with W90 mutated to alanine (W90A) and in the fully-saturated state with target peptide bound to probe the interaction between helix 4 (H4) and the remaining helices
Summary
S100A1 is a Ca2+ binding protein that is implicated in cardiac and neurological functions (Wright et al, 2009b). S100A1 expressed in cardiac tissue is believed to manage contractile behavior either through modulating cytosolic Ca2+ (Kraus et al, 2009), which triggers the initiation of contraction, or through modulating properties of the contractile fibers of the myofilament. For the latter, there is evidence that Ca2+-loaded S100A1 disrupts interactions between actins of the thin filament and titin (Gutierrez-Cruz et al, 2001; Granzier et al, 2010; Yamasaki et al, 2011). In vitro assays indicate S100A1 binds targets at Ca2+ levels considerably above physiological Ca2+ concentrations, which casts doubts on the ability of wildtype (WT) S100A1 to contribute to titin’s management of contractile properties
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