Please use this identifier to cite or link to this item:
http://hdl.handle.net/1843/46401
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 |
Files in This Item:
File | Description | Size | Format | |
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Allosteric Transmission along a Loosely Structured Backbone.pdf | 4.52 MB | Adobe PDF | View/Open |
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