The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation

Página do item simplificado
dc.creatorJamie R. Johnston
dc.creatorEinat Birk
dc.creatorNili Zucker
dc.creatorJerson Lima da Silva
dc.creatorP. Bryant Chase
dc.creatorJose Renato Pinto
dc.creatorMaicon Landim-vieira
dc.creatorMayra de Amorim Marques
dc.creatorGuilherme A. P. de Oliveira
dc.creatorDavid Gonzalez-martinez
dc.creatorAdolfo Henrique de Moraes Silva
dc.creatorHuan he
dc.creatorAnwar Iqbal
dc.creatorYael Wilnai
dc.date.accessioned2022-10-18T23:42:24Z
dc.date.accessioned2025-09-09T01:31:25Z
dc.date.available2022-10-18T23:42:24Z
dc.date.issued2019-12-27
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1074/jbc.RA119.011177
dc.identifier.issn0021-9258
dc.identifier.urihttps://hdl.handle.net/1843/46345
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofJournal of Biological Chemistry
dc.rightsAcesso Aberto
dc.subjectRessonância magnética nuclear
dc.subjectMiocárdio
dc.subjectMiocárdio
dc.subjectDoenças
dc.subject.otherCardiac muscle contractile
dc.subject.otherContractile protein
dc.subject.otherProtein dynamic
dc.subject.otherStructure–function
dc.subject.otherCardiovascular disease
dc.subject.otherCardiomyopathy
dc.subject.otherCross-bridges
dc.subject.otherNMR
dc.subject.otherTroponin
dc.subject.otherEspectroscopia de ressonância nuclear
dc.subject.otherRessonância magnética nuclear
dc.titleThe intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation
dc.title.alternativeModulation of myocardial contraction by TnC–TnT interaction
dc.typeArtigo de periódico
local.citation.epage20069
local.citation.issue52
local.citation.spage20054
local.citation.volume294
local.description.resumoAberrant 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.
local.identifier.orcidhttps://orcid.org/0000-0002-6696-8888
local.identifier.orcidhttps://orcid.org/0000-0002-0063-5888
local.identifier.orcidhttps://orcid.org/0000-0001-9523-9441
local.identifier.orcidhttps://orcid.org/0000-0001-9701-561X
local.identifier.orcidhttps://orcid.org/0000-0001-9092-4976
local.identifier.orcidhttps://orcid.org/0000-0002-4131-4634
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://www.sciencedirect.com/science/article/pii/S0021925820300259

Arquivos

Pacote original

Agora exibindo 1 - 1 de 1
Imagem de Miniatura
Nome:
The intrinsically disordered C terminus of troponin T binds to.pdf
Tamanho:
2.23 MB
Formato:
Adobe Portable Document Format
Baixar

Licença do pacote

Agora exibindo 1 - 1 de 1
Imagem de Miniatura
Nome:
License.txt
Tamanho:
1.99 KB
Formato:
Plain Text
Descrição:
Baixar

Coleções

Artigo de Periódico

Logo UFMG