The effect of Mg 2+ on Ca 2+ binding to cardiac troponin C in hypertrophic cardiomyopathy associated TNNC1 variants.

Autor: Rayani K; Molecular Cardiac Physiology Group, Simon Fraser University, Burnaby, Canada., Hantz ER; Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, USA., Haji-Ghassemi O; Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, Canada., Li AY; Molecular Cardiac Physiology Group, Simon Fraser University, Burnaby, Canada., Spuches AM; Department of Chemistry, 300 Science and Technology, East Carolina University, Greenville, NC, USA., Van Petegem F; Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, Canada., Solaro RJ; Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago, USA., Lindert S; Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, USA., Tibbits GF; Molecular Cardiac Physiology Group, Simon Fraser University, Burnaby, Canada.; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.; BC Children's Hospital Research Institute, Vancouver, Canada.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2022 Dec; Vol. 289 (23), pp. 7446-7465. Date of Electronic Publication: 2022 Aug 02.
DOI: 10.1111/febs.16578
Abstrakt: Cardiac troponin C (cTnC) is the critical Ca 2+ -sensing component of the troponin complex. Binding of Ca 2+ to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)-associated TNNC1 variants generally induce a greater degree and duration of Ca 2+ binding, which may underly the hypertrophic phenotype. Regulation of contraction has long been thought to occur exclusively through Ca 2+ binding to site II of cTnC. However, work by several groups including ours suggest that Mg 2+ , which is several orders of magnitude more abundant in the cell than Ca 2+ , may compete for binding to the same cTnC regulatory site. We previously used isothermal titration calorimetry (ITC) to demonstrate that physiological concentrations of Mg 2+ may decrease site II Ca 2+ -binding in both N-terminal and full-length cTnC. Here, we explore the binding of Ca 2+ and Mg 2+ to cTnC harbouring a series of TNNC1 variants thought to be causal in HCM. ITC and thermodynamic integration (TI) simulations show that A8V, L29Q and A31S elevate the affinity for both Ca 2+ and Mg 2+ . Further, L48Q, Q50R and C84Y that are adjacent to the EF hand binding motif of site II have a more significant effect on affinity and the thermodynamics of the binding interaction. To the best of our knowledge, this work is the first to explore the role of Mg 2+ in modifying the Ca 2+ affinity of cTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg 2+ both at baseline and when elevated on modifying the Ca 2+ binding properties of cTnC and the subsequent conformational changes which precede cardiac contraction.
(© 2022 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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