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Please use this identifier to cite or link to this item: http://hdl.handle.net/1843/46401
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dc.creatorMayra de Amorim Marquespt_BR
dc.creatorGuilherme Augusto Piedade de Oliveirapt_BR
dc.creatorJose Renato Pintopt_BR
dc.creatorAdolfo Henrique de Moraes Silvapt_BR
dc.creatorAnwar Iqbalpt_BR
dc.creatorMariana Torquato Quezado de Magalhãespt_BR
dc.creatorJamila Monteiro dos Santospt_BR
dc.creatorMurilo Martins Pedrotept_BR
dc.creatorMartha Meriwether Sorensonpt_BR
dc.creatorJerson Lima da Silvapt_BR
dc.date.accessioned2022-10-19T17:34:06Z-
dc.date.available2022-10-19T17:34:06Z-
dc.date.issued2017-02-10-
dc.citation.volume292pt_BR
dc.citation.issue6pt_BR
dc.citation.spage2379pt_BR
dc.citation.epage2394pt_BR
dc.identifier.doihttps://doi.org/10.1074/jbc.M116.765362pt_BR
dc.identifier.issn0021-9258pt_BR
dc.identifier.urihttp://hdl.handle.net/1843/46401-
dc.description.resumoHypertrophic 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.pt_BR
dc.format.mimetypepdfpt_BR
dc.languageengpt_BR
dc.publisherUniversidade Federal de Minas Geraispt_BR
dc.publisher.countryBrasilpt_BR
dc.publisher.departmentICX - DEPARTAMENTO DE QUÍMICApt_BR
dc.publisher.initialsUFMGpt_BR
dc.relation.ispartofJournal of Biological Chemistrypt_BR
dc.rightsAcesso Abertopt_BR
dc.subjectCalcium-binding proteinpt_BR
dc.subjectCardiomyopathypt_BR
dc.subjectNuclear magnetic resonance (NMR)pt_BR
dc.subjectProtein structurept_BR
dc.subjectSmall-angle X-ray scattering (SAXS)pt_BR
dc.subjectTroponinpt_BR
dc.subject.otherCálciopt_BR
dc.subject.otherProteínaspt_BR
dc.subject.otherMiocárdiopt_BR
dc.subject.otherDoençaspt_BR
dc.subject.otherRessonância magnética nuclearpt_BR
dc.subject.otherCoraçãopt_BR
dc.subject.otherContraçãopt_BR
dc.titleAllosteric transmission along a loosely structured backbone allows a cardiac troponin C mutant to function with only one Ca2+ ionpt_BR
dc.typeArtigo de Periódicopt_BR
dc.url.externahttps://www.sciencedirect.com/science/article/pii/S0021925820424949pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0003-4912-0233pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0002-4131-4634pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0001-6744-9572pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0001-9822-4050pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0001-9523-9441pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0002-0063-5888pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0002-3344-4084pt_BR
dc.identifier.orcidhttps://orcid.org/0000-0001-6002-9794pt_BR
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