Binding of Calcium and Magnesium to Cardiac Troponin C
Rayani, K.; Seffernick, J. T.; Li, Y. A.; Davis, J. P.; Spuches, A.; Petegem, F. V.; Solaro, R. J.; Lindert, S.; Tibbits, G. F.
Show abstract
Cardiac troponin C (cTnC) is the Ca2+-sensing component of the thin filament. It contains structural sites (III/IV) which bind both Ca2+ and Mg2+, and a regulatory site (II) that has been thought to bind only Ca2+. The latter binding initiates a series of conformational changes that culminate in force production. We have quantified the interaction between site II and Ca2+/Mg2+ through Isothermal Titration Calorimetry and Thermodynamic Integration simulations. Direct and competitive binding titrations using wild type and a double mutant that significantly reduces binding to site II demonstrated that physiologically relevant concentrations of both Ca2+/Mg2+ interact with the same locus. Cytosolic free Mg2+ (~1 mM) could occupy a significant population of available site II, as this concentration of Mg2+ decreased the affinity for Ca2+ 1.4-fold. Interaction of Mg2+ with site II of cTnC likely has important functional consequences for the heart at baseline and in diseased states which decrease or increase availability of Mg2+ such as secondary hyperparathyroidism or ischemia, respectively.
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