The effect of Mg2+ on Ca2+ binding to cardiac troponin C in hypertrophic cardiomyopathy associated TNNC1 variants.
FEBS J
; 289(23): 7446-7465, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-35838319
ABSTRACT
Cardiac troponin C (cTnC) is the critical Ca2+ -sensing component of the troponin complex. Binding of Ca2+ 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 Ca2+ binding, which may underly the hypertrophic phenotype. Regulation of contraction has long been thought to occur exclusively through Ca2+ binding to site II of cTnC. However, work by several groups including ours suggest that Mg2+ , which is several orders of magnitude more abundant in the cell than Ca2+ , may compete for binding to the same cTnC regulatory site. We previously used isothermal titration calorimetry (ITC) to demonstrate that physiological concentrations of Mg2+ may decrease site II Ca2+ -binding in both N-terminal and full-length cTnC. Here, we explore the binding of Ca2+ and Mg2+ 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 Ca2+ and Mg2+ . 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 Mg2+ in modifying the Ca2+ affinity of cTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg2+ both at baseline and when elevated on modifying the Ca2+ binding properties of cTnC and the subsequent conformational changes which precede cardiac contraction.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cardiomiopatia Hipertrófica
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
FEBS J
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Canadá