期刊
FASEB JOURNAL
卷 30, 期 5, 页码 1849-1864出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201500048
关键词
redox proteomics; post-translational modifications; cross-bridge cycling; contractile function; cardiac disease
资金
- German Center for Cardiovascular Research (DZHK)
- German Ministry of Research and Education (BMBF)
- Deutsche Forschungsgemeinschaft (DFG) [CU 53/2-1]
- Faculty of Medicine-University medical Center Hamburg-Eppendorf
- Werner Otto Foundation
- DFG [SFB815]
- U.S. National Institutes of Health, National Heart, Lung and Blood Institute [R01HL105826, K02HL114749]
- MRC [G0600785, G1000458, G0700320, MR/L009684/1, MR/K003232/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C503646/1] Funding Source: researchfish
- British Heart Foundation [PG/10/98/28655, PG/15/26/31373, RG/12/12/29872, PG/13/13/30018, FS/11/45/28859] Funding Source: researchfish
- Medical Research Council [G0600785, MR/K003232/1, G1000458, 998501, MR/L009684/1, G0700320] Funding Source: researchfish
Cardiac myosin-binding protein C (cMyBPC) 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 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.
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