S-glutathiolation of cardiac myosin-binding protein C in contractile dysfunction

• Applicant: Professorin Dr. Friederike Cuello
• Subject Area: Pharmacology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252120716

Heart failure (HF) is a clinical syndrome that arises from diverse causes and remains one of the leading factors of human mortality. Understanding the molecular mechanisms that govern cardiac function and their modifications during disease development is likely to identify key elements that might provide targets for novel treatment strategies. Cardiac myosin-binding protein C (cMyBP-C) is a thick filament-associated protein involved in the maintenance of sarcomere integrity and in the regulation of contraction and relaxation. Importantly, phosphorylation of cMyBP-C within the N-terminal M-domain leads to acceleration of cross-bridge cycling kinetics and force generation through removal of a structural constraint on myosin heads. Furthermore, phosphorylation has been described to protect myofilaments from enzymatic degradation under disease conditions, such as ischemia/reperfusion. We have obtained evidence that cMyBP-C is subject to oxidative post-translational modification, namely S-glutathiolation. We mapped one S-glutathiolation site within the C1-M-C2 domain of cMyBP-C to cysteine 249, in close vicinity to the phosphorylation-regulated M-domain. However, whether S-glutathiolation of cMyBP-C at Cys249 impacts on cardiac myocyte and whole heart function and the interplay and balance between phosphorylation and oxidation in health and disease warrants thorough investigation. Therefore, we propose (1) to explore the effect of S-glutathiolation on cMyBP-C function in vitro, (2) to elucidate a potential crosstalk between phosphorylation and oxidation and (3) to investigate the impact of S-glutathiolation on cMyBP-C function in vivo under (patho)physiological conditions. The project will lead to a better understanding of the molecular mechanisms underlying contractile dysfunction and may provide perspective to advance the development of novel treatment strategies.

• DFG Programme: Research Grants
• Participating Person: Konstantina Stathopoulou, Ph.D.