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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 Cys(249), which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca(2+)-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., Schröder, 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.

SUBMITTER: Stathopoulou K 

PROVIDER: S-EPMC4836368 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Stathopoulou Konstantina K   Wittig Ilka I   Heidler Juliana J   Piasecki Angelika A   Richter Florian F   Diering Simon S   van der Velden Jolanda J   Buck Friedrich F   Donzelli Sonia S   Schröder Ewald E   Wijnker Paul J M PJ   Voigt Niels N   Dobrev Dobromir D   Sadayappan Sakthivel S   Eschenhagen Thomas T   Carrier Lucie L   Eaton Philip P   Cuello Friederike F  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20160202 5


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  ...[more]

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