Key result
Physiologic Mg2+ reduces Ca2+ affinity of cTnC by ~1.4-fold.
Why the study?
Regulatory site II of cardiac troponin C has been thought to bind only Ca2+, prompting quantification of its interaction with Ca2+ and Mg2+.
Effect estimate: 1.4-fold decrease in Ca2+ affinity
Physiologically relevant concentrations of Mg2+ can bind to the regulatory site II of cardiac troponin C, decreasing its affinity for Ca2+, which challenges the previous assumption that site II binds only Ca2+.
Challenges assumption of Ca2+-exclusive binding at troponin C site II; leaves open in vivo cardiac effects.
Cardiac troponin C (cTnC) is the Ca 2+ -sensing component of the thin filament. It contains structural sites (III/IV) which bind both Ca 2+ and Mg 2+ , and a regulatory site (II) that has been thought to bind only Ca 2+ . The latter binding initiates a series of conformational changes that culminate in force production. We have quantified the interaction between site II and Ca 2+ /Mg 2+ 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 Ca 2+ /Mg 2+ interact with the same locus. Cytosolic free Mg 2+ (~1 mM) could occupy a significant population of available site II, as this concentration of Mg 2+ decreased the affinity for Ca 2+ 1.4-fold. Interaction of Mg 2+ 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 Mg 2+ such as secondary hyperparathyroidism or ischemia, respectively.
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Rayani et al. (2020) studied Cardiac troponin C binding. Calcium and Magnesium was evaluated on Interaction between site II of cTnC and Ca2+/Mg2+ (1.4-fold decrease in Ca2+ affinity). Physiologically relevant concentrations of Mg2+ (~1 mM) interact with the regulatory site II of cardiac troponin C, decreasing its affinity for Ca2+ by 1.4-fold.
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