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Type:	Artigo de Periódico
Title:	Allosteric transmission along a loosely structured backbone allows a cardiac troponin C mutant to function with only one Ca2+ ion
Authors:	Mayra de Amorim Marques Guilherme Augusto Piedade de Oliveira Jose Renato Pinto Adolfo Henrique de Moraes Silva Anwar Iqbal Mariana Torquato Quezado de Magalhães Jamila Monteiro dos Santos Murilo Martins Pedrote Martha Meriwether Sorenson Jerson Lima da Silva
Abstract:	Hypertrophic cardiomyopathy (HCM) is one of the most common cardiomyopathies and a major cause of sudden death in young athletes. The Ca2+ sensor of the sarcomere, cardiac troponin C (cTnC), plays an important role in regulating muscle contraction. Although several cardiomyopathy-causing mutations have been identified in cTnC, the limited information about their structural defects has been mapped to the HCM phenotype. Here, we used high-resolution electron-spray ionization mass spectrometry (ESI-MS), Carr-Purcell-Meiboom-Gill relaxation dispersion (CPMG-RD), and affinity measurements of cTnC for the thin filament in reconstituted papillary muscles to provide evidence of an allosteric mechanism in mutant cTnC that may play a role to the HCM phenotype. We showed that the D145E mutation leads to altered dynamics on a μs-ms time scale and deactivates both of the divalent cation-binding sites of the cTnC C-domain. CPMG-RD captured a low populated protein-folding conformation triggered by the Glu-145 replacement of Asp. Paradoxically, although D145E C-domain was unable to bind Ca2+, these changes along its backbone allowed it to attach more firmly to thin filaments than the wild-type isoform, providing evidence for an allosteric response of the Ca2+-binding site II in the N-domain. Our findings explain how the effects of an HCM mutation in the C-domain reflect up into the N-domain to cause an increase of Ca2+ affinity in site II, thus opening up new insights into the HCM phenotype.
Subject:	Cálcio Proteínas Miocárdio Doenças Ressonância magnética nuclear Coração Contração
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.M116.765362
URI:	http://hdl.handle.net/1843/46401
Issue Date:	10-Feb-2017
metadata.dc.url.externa:	https://www.sciencedirect.com/science/article/pii/S0021925820424949
metadata.dc.relation.ispartof:	Journal of Biological Chemistry
Appears in Collections:	Artigo de Periódico

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