title: Molecular Basis of S100A1 Activation at Saturating and Subsaturating Calcium Concentrations.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, Kentucky.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Scott
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, Kentucky. Electronic address: pkekeneshuskey@uky.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kekenes-Huskey
mesh_terms: D001059:Apoproteins / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology*; D002614:Chelating Agents / Q000378:metabolism; D020832:EF Hand Motifs; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions; D009682:Magnetic Resonance Spectroscopy; D010100:Oxygen / Q000378:metabolism; D025341:Principal Component Analysis; D017433:Protein Structure, Secondary; D009418:S100 Proteins / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D013997:Time Factors
chemical_list: D001059:Apoproteins; D002614:Chelating Agents; D007477:Ions; D009418:S100 Proteins; C110294:S100A1 protein; D010100:Oxygen; D002118:Calcium