Research

As its long-term goal, the Sadayappan Lab aims to delineate the role of myosin binding protein-C (MyBP- C) structure, regulation and function in striated muscles of both cardiac and skeletal tissues. MyBP-C is localized in the inner two-thirds of the A band, the so-called C zone. Importantly, in humans, mutations in the cardiac MyBP-C gene are associated with familial hypertrophic and dilated cardiomyopathy, accounting for 35% of all mutations linked to cardiomyopathies. To prevent the development of either hypertrophic or dilated cardiomyopathy at the early stage, the causal defect in the gene encoding cMyBP-C protein must be elucidated. MyBP-C binds to titin, myosin, actin and tropomyosin filaments as a transverse filament protein connecting both thick and thin filaments in the sarcomere. MyBP-C has three isoforms encoded by three distinct genes: fast-skeletal, slow-skeletal and cardiac. The cardiac isoform differs from the skeletal isoform by having an extra Ig domain at the N-terminus (C0), three phosphorylation sites within the MyBP-C motif region and a module (C5) that has an inserted loop of 28 residues. However, the differential roles of these isoforms in striated muscles remain unclear. Importantly, studies have shown that the cardiac isoform undergoes several different post-translational modifications, such as phosphorylation, glutathionylation, acetylation, carboxylation, O-GlcNAcylation and Citrullination, indicating that cMyBP-C is a regulatory protein and a central target of sarcomeric signaling. Some of these modifications alter MyBP-C proteolysis during muscle injury. Exactly how these modifications alter sarcomere regulation, structure and function is still unclear. Therefore, Sadayappan is committed to exploring the regulation of MyBP-C in various preclinical and clinical conditions using in vitro, ex vivo and in vivo approaches.

References:

• Kuster DW and Sadayappan S. MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation. Pflügers Archiv. 2014 466(2):207-13.
• Sadayappan S, de Tombe PP. Cardiac myosin binding protein-C as a central target of cardiac sarcomere signaling: a special mini review series. Pflugers Arch. 2014 466(2):195-200.
• Sadayappan S, de Tombe PP. Cardiac myosin binding protein-C: redefining its structure and function. Biophys Rev. 2012 Jun 1;4(2):93-106.
• Sadayappan S.Cardiac myosin binding protein-C: a potential early-stage, cardiac-specific biomarker of ischemic-reperfusion injury. Biomarkers Med. 2012 6(1), 69–72.
• Barefield D and Sadayappan S. Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J Mol Cell Cardiol. 2010 48(5):866-875.
• Sadayappan Sand Robbins J. The death of transcriptional chauvinism in the control and regulation of cardiac contractility. Ann N Y Acad Sci. 2008; 1123:1-9