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Type:	Artigo de Periódico
Title:	The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation
Other Titles:	Modulation of myocardial contraction by TnC–TnT interaction
Authors:	Jamie R. Johnston Einat Birk Nili Zucker Jerson Lima da Silva P. Bryant Chase Jose Renato Pinto Maicon Landim-vieira Mayra de Amorim Marques Guilherme A. P. de Oliveira David Gonzalez-martinez Adolfo Henrique de Moraes Silva Huan he Anwar Iqbal Yael Wilnai
Abstract:	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.
Subject:	Ressonância magnética nuclear Miocárdio Miocárdio Doenças
language:	eng
metadata.dc.publisher.country:	Brasil
Publisher:	Universidade Federal de Minas Gerais
Publisher Initials:	UFMG
metadata.dc.publisher.department:	ICX - DEPARTAMENTO DE QUÍMICA
Rights:	Acesso Aberto
metadata.dc.identifier.doi:	https://doi.org/10.1074/jbc.RA119.011177
URI:	http://hdl.handle.net/1843/46345
Issue Date:	27-Dec-2019
metadata.dc.url.externa:	https://www.sciencedirect.com/science/article/pii/S0021925820300259
metadata.dc.relation.ispartof:	Journal of Biological Chemistry
Appears in Collections:	Artigo de Periódico

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