دورية أكاديمية
Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy.
| العنوان: | Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy. |
|---|---|
| المؤلفون: | Marques MA; Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro 373 Carlos Chagas Filho Av, Room: E-10 Rio de Janeiro RJ 21941-902 Brazil gaugusto@bioqmed.ufrj.br +55-21-3938-6756., Landim-Vieira M; Department of Biomedical Sciences, Florida State University, College of Medicine 1115 West Call Street, Room: 1370 (lab) - 1350-H (office) Tallahassee FL 32306 USA jose.pinto@med.fsu.edu +1-850-645-0016., Moraes AH; Department of Chemistry, Federal University of Minas Gerais Belo Horizonte MG Brazil., Sun B; Department of Cell and Molecular Physiology, Loyola University Chicago Maywood IL USA., Johnston JR; Department of Biomedical Sciences, Florida State University, College of Medicine 1115 West Call Street, Room: 1370 (lab) - 1350-H (office) Tallahassee FL 32306 USA jose.pinto@med.fsu.edu +1-850-645-0016., Dieseldorff Jones KM; Department of Biomedical Sciences, Florida State University, College of Medicine 1115 West Call Street, Room: 1370 (lab) - 1350-H (office) Tallahassee FL 32306 USA jose.pinto@med.fsu.edu +1-850-645-0016., Cino EA; Department of Biochemistry and Immunology, Federal University of Minas Gerais Belo Horizonte MG Brazil., Parvatiyar MS; Department of Nutrition, Food and Exercise Sciences, Florida State University Tallahassee FL USA., Valera IC; Department of Nutrition, Food and Exercise Sciences, Florida State University Tallahassee FL USA., Silva JL; Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro 373 Carlos Chagas Filho Av, Room: E-10 Rio de Janeiro RJ 21941-902 Brazil gaugusto@bioqmed.ufrj.br +55-21-3938-6756., Galkin VE; Department of Physiological Sciences, Eastern Virginia Medical School Norfolk VA USA., Chase PB; Department of Biological Science, Florida State University Tallahassee FL USA., Kekenes-Huskey PM; Department of Cell and Molecular Physiology, Loyola University Chicago Maywood IL USA., de Oliveira GAP; Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro 373 Carlos Chagas Filho Av, Room: E-10 Rio de Janeiro RJ 21941-902 Brazil gaugusto@bioqmed.ufrj.br +55-21-3938-6756., Pinto JR; Department of Biomedical Sciences, Florida State University, College of Medicine 1115 West Call Street, Room: 1370 (lab) - 1350-H (office) Tallahassee FL 32306 USA jose.pinto@med.fsu.edu +1-850-645-0016. |
| المصدر: | Chemical science [Chem Sci] 2021 Apr 29; Vol. 12 (21), pp. 7308-7323. Date of Electronic Publication: 2021 Apr 29. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Royal Society of Chemistry Country of Publication: England NLM ID: 101545951 Publication Model: Electronic Cited Medium: Print ISSN: 2041-6520 (Print) Linking ISSN: 20416520 NLM ISO Abbreviation: Chem Sci Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, UK : Royal Society of Chemistry, [2010]- |
| مستخلص: | Cardiac TnC (cTnC) is highly conserved among mammals, and genetic variants can result in disease by perturbing Ca 2+ -regulation of myocardial contraction. Here, we report the molecular basis of a human mutation in cTnC's αD-helix ( TNNC1 -p.C84Y) that impacts conformational dynamics of the D/E central-linker and sampling of discrete states in the N-domain, favoring the "primed" state associated with Ca 2+ binding. We demonstrate cTnC's αD-helix normally functions as a central hub that controls minimally frustrated interactions, maintaining evolutionarily conserved rigidity of the N-domain. αD-helix perturbation remotely alters conformational dynamics of the N-domain, compromising its structural rigidity. Transgenic mice carrying this cTnC mutation exhibit altered dynamics of sarcomere function and hypertrophic cardiomyopathy. Together, our data suggest that disruption of evolutionary conserved molecular frustration networks by a myofilament protein mutation may ultimately compromise contractile performance and trigger hypertrophic cardiomyopathy. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.) |
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| معلومات مُعتمدة: | F31 HL137408 United States HL NHLBI NIH HHS; R01 HL128683 United States HL NHLBI NIH HHS; R35 GM124977 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20210624 Latest Revision: 20240505 |
| رمز التحديث: | 20240505 |
| مُعرف محوري في PubMed: | PMC8171346 |
| DOI: | 10.1039/d1sc01886h |
| PMID: | 34163821 |
| قاعدة البيانات: | MEDLINE |
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