Allosteric transmission along a loosely structured backbone allows a cardiac troponin C mutant to function with only one Ca2+ ion

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dc.creatorMayra de Amorim Marques
dc.creatorGuilherme Augusto Piedade de Oliveira
dc.creatorJose Renato Pinto
dc.creatorAdolfo Henrique de Moraes Silva
dc.creatorAnwar Iqbal
dc.creatorMariana Torquato Quezado de Magalhães
dc.creatorJamila Monteiro dos Santos
dc.creatorMurilo Martins Pedrote
dc.creatorMartha Meriwether Sorenson
dc.creatorJerson Lima da Silva
dc.date.accessioned2022-10-19T17:34:06Z
dc.date.accessioned2025-09-09T00:07:02Z
dc.date.available2022-10-19T17:34:06Z
dc.date.issued2017-02-10
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1074/jbc.M116.765362
dc.identifier.issn0021-9258
dc.identifier.urihttps://hdl.handle.net/1843/46401
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofJournal of Biological Chemistry
dc.rightsAcesso Aberto
dc.subjectCálcio
dc.subjectProteínas
dc.subjectMiocárdio
dc.subjectDoenças
dc.subjectRessonância magnética nuclear
dc.subjectCoração
dc.subjectContração
dc.subject.otherCalcium-binding protein
dc.subject.otherCardiomyopathy
dc.subject.otherNuclear magnetic resonance (NMR)
dc.subject.otherProtein structure
dc.subject.otherSmall-angle X-ray scattering (SAXS)
dc.subject.otherTroponin
dc.titleAllosteric transmission along a loosely structured backbone allows a cardiac troponin C mutant to function with only one Ca2+ ion
dc.typeArtigo de periódico
local.citation.epage2394
local.citation.issue6
local.citation.spage2379
local.citation.volume292
local.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.
local.identifier.orcidhttps://orcid.org/0000-0003-4912-0233
local.identifier.orcidhttps://orcid.org/0000-0002-4131-4634
local.identifier.orcidhttps://orcid.org/0000-0001-6744-9572
local.identifier.orcidhttps://orcid.org/0000-0001-9822-4050
local.identifier.orcidhttps://orcid.org/0000-0001-9523-9441
local.identifier.orcidhttps://orcid.org/0000-0002-0063-5888
local.identifier.orcidhttps://orcid.org/0000-0002-3344-4084
local.identifier.orcidhttps://orcid.org/0000-0001-6002-9794
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://www.sciencedirect.com/science/article/pii/S0021925820424949

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