Molecular Basis of S100A1 Activation at Saturating and Subsaturating Calcium Concentrations.

TitleMolecular Basis of S100A1 Activation at Saturating and Subsaturating Calcium Concentrations.
Publication TypeJournal Article
Year of Publication2016
JournalBiophysical journal
Date Published2016

The S100A1 protein mediates a wide variety of physiological processes through its binding of calcium (Ca(2+)) and endogenous target proteins. S100A1 presents two Ca(2+)-binding domains: a high-affinity "canonical" EF (cEF) hand and a low-affinity "pseudo" EF (pEF) hand. Accumulating evidence suggests that both Ca(2+)-binding sites must be saturated to stabilize an open state conducive to peptide recognition, yet the pEF hand's low affinity limits Ca(2+) binding at normal physiological concentrations. To understand the molecular basis of Ca(2+) binding and open-state stabilization, we performed 100 ns molecular dynamics simulations of S100A1 in the apo/holo (Ca(2+)-free/bound) states and a half-saturated state, for which only the cEF sites are Ca(2+)-bound. Our simulations indicate that the pattern of oxygen coordination about Ca(2+) in the cEF relative to the pEF site contributes to the former's higher affinity, whereas Ca(2+) binding strongly reshapes the protein's conformational dynamics by disrupting β-sheet coupling between EF hands. Moreover, modeling of the half-saturated configuration suggests that the open state is unstable and reverts toward a closed state in the absence of the pEF Ca(2+) ion. These findings indicate that Ca(2+) binding at the cEF site alone is insufficient to stabilize opening; thus, posttranslational modification of the protein may be required for target peptide binding at subsaturating intracellular Ca(2+) levels.

Short TitleBiophys J
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