S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure Journal Article

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Authors: Stathopoulou, K.; Wittig, I.; Heidler, J.; Piasecki, A.; Richter, F.; Diering, S.; van der Velden, J.; Buck, F.; Donzelli, S.; Schroder, E.; Wijnker, P. J.; Voigt, N.; Dobrev, D.; Sadayappan, S; Eschenhagen, T.; Carrier, L.; Eaton, P.; Cuello, F.
Article Title: S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure
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.-Stathopoulou K., Wittig, I., Heidler, J., Piasecki, A., Richter, F. Diering, S., van der Velden, J., Buck, F., Donzelli, S., Schroder, E., Wijnker, P. J. M., Voigt, N., Dobrev, D., Sadayappan, S., Eschenhagen, T., Carrier, L., Eaton, P., Cuello, F. S-glutathiolation impairs phosphoregulation and function of cardiac myosin-binding protein C in human heart failure.
Journal Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860; 0892-6638
Publisher: Unknown  
Date Published: 2016
Language: ENG
DOI/URL:

fj.201500048
Notes: LR: 20160322; CI: (c) FASEB.; GR: PG/10/98/28655/British Heart Foundation/United Kingdom; GR: RG/12/12/29872/British Heart Foundation/United Kingdom; GR: G0600785/Medical Research Council/United Kingdom; JID: 8804484; OTO: NOTNLM; aheadofprint