The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation
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Universidade Federal de Minas Gerais
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Artigo de periódico
Título alternativo
Modulation of myocardial contraction by TnC–TnT interaction
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Membros da banca
Resumo
Aberrant regulation of myocardial force production represents an early biomechanical defect associated with sarcomeric cardiomyopathies, but the molecular mechanisms remain poorly defined. Here, we evaluated the pathogenicity of a previously unreported sarcomeric gene variant identified in a pediatric patient with sporadic dilated cardiomyopathy, and we determined a molecular mechanism. Trio whole-exome sequencing revealed a de novo missense variant in TNNC1 that encodes a p.I4M substitution in the N-terminal helix of cardiac troponin C (cTnC). Reconstitution of this human cTnC variant into permeabilized porcine cardiac muscle preparations significantly decreases the magnitude and rate of isometric force generation at physiological Ca2+-activation levels. Computational modeling suggests that this inhibitory effect can be explained by a decrease in the rates of cross-bridge attachment and detachment. For the first time, we show that cardiac troponin T (cTnT), in part through its intrinsically disordered C terminus, directly binds to WT cTnC, and we find that this cardiomyopathic variant displays tighter binding to cTnT. Steady-state fluorescence and NMR spectroscopy studies suggest that this variant propagates perturbations in cTnC structural dynamics to distal regions of the molecule. We propose that the intrinsically disordered C terminus of cTnT directly interacts with the regulatory N-domain of cTnC to allosterically modulate Ca2+ activation of force, perhaps by controlling the troponin I switching mechanism of striated muscle contraction. Alterations in cTnC–cTnT binding may compromise contractile performance and trigger pathological remodeling of the myocardium.
Abstract
Assunto
Ressonância magnética nuclear, Miocárdio, Miocárdio, Doenças
Palavras-chave
Cardiac muscle contractile, Contractile protein, Protein dynamic, Structure–function, Cardiovascular disease, Cardiomyopathy, Cross-bridges, NMR, Troponin, Espectroscopia de ressonância nuclear, Ressonância magnética nuclear
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https://www.sciencedirect.com/science/article/pii/S0021925820300259