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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Biol+Chem 2021 ; 296 (ä): 100350 Nephropedia Template TP
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Binding of calcium and magnesium to human cardiac troponin C #MMPMID33548225
Rayani K; Seffernick J; Li AY; Davis JP; Spuches AM; Van Petegem F; Solaro RJ; Lindert S; Tibbits GF
J Biol Chem 2021[Jan]; 296 (ä): 100350 PMID33548225show ga
Cardiac muscle thin filaments are composed of actin, tropomyosin, and troponin that change conformation in response to Ca(2+) binding, triggering muscle contraction. Human cardiac troponin C (cTnC) is the Ca(2+)-sensing component of the thin filament. It contains structural sites (III/IV) that bind both Ca(2+) and Mg(2+) and a regulatory site (II) that has been thought to bind only Ca(2+). Binding of Ca(2+) at this site initiates a series of conformational changes that culminate in force production. However, the mechanisms that underpin the regulation of binding at site II remain unclear. Here, 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 with WT N-terminal cTnC and full-length cTnC indicate that physiologically relevant concentrations of both Ca(2+)/Mg(2+) interacted with the same locus. Moreover, the D67A/D73A N-terminal cTnC construct in which two coordinating residues within site II were removed was found to have significantly reduced affinity for both cations. In addition, 1 mM Mg(2+) caused a 1.4-fold lower affinity for Ca(2+). These experiments strongly suggest that cytosolic-free Mg(2+) occupies a significant population of the available site II. Interaction of Mg(2+) with site II of cTnC likely has important functional consequences for the heart both at baseline as well as in diseased states that decrease or increase the availability of Mg(2+), such as secondary hyperparathyroidism or ischemia, respectively.