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S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.
- Source :
-
FASEB Journal . May2016, Vol. 30 Issue 5, p1849-1864. 16p. - Publication Year :
- 2016
-
Abstract
- Cardiac myosin-binding protein C (cMyBP-C) regulates actin-myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific S-glutathiolation sites in cMyBP-C in donor and patient samples, respectively. Among those, a cysteine cluster in the vicinity of the regulatory phosphorylation sites within the myosin S2 interaction domain C1-M-C2 was identified and showed enhanced S-glutathiolation in patients. In vitro S-glutathiolation of recombinant cMyBP-C C1-M-C2 occurred predominantly at Cys249, which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca2+-activated force development in ventricular myocytes from wild-type, but not those from Mybpc3-targeted knockout mice. These oxidation events abrogate protein kinase-mediated phosphorylation of cMyBP-C and therefore potentially contribute to the reduction of its phosphorylation and the contractile dysfunction observed in human heart failure. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08926638
- Volume :
- 30
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- FASEB Journal
- Publication Type :
- Academic Journal
- Accession number :
- 115098135
- Full Text :
- https://doi.org/10.1096/fj.201500048