MRC PhD students

Amsha is a PhD student investigating the N-terminal interactions of cardiac Myosin Binding Protein C (cMyBPC) under defined phosphorylation states. The gene encoding cMyBPC is most commonly mutated in patients with one of the most frequently occurring inherited cardiac disorders, hypertrophic cardiomyopathy (HCM). HCM is an autosomal dominant familial disease that affects about one in 500 individuals and has been identified as the most common cause of sudden death in young adults. Over the years mutations in genes that encode for proteins that make up the cardiac muscle sarcomere have been identified as causative of this disease.  MyBPC is an integral part of vertebrate striated muscle, but its precise roles and quaternary arrangement in the sarcomere are incompletely understood, thus limiting the functional study of this protein and hence the understanding of the mechanisms by which defects in this protein cause disease. The function and ligands of the C-terminal of cMyBPC have thus far been defined, but those of the N-terminal are still largely unknown. The N-terminal (between domains C1 and C2) houses three phosphorylation sites which are crucial in the regulation of cardiac contractility. Previous work by our group has proposed the “trimeric collar structure” around the thick filament as the quaternary arrangement of cMyBPC in the sarcomere. It is further proposed that this collar is dynamic formed and released upon cMyBPC phosphorylation. By defining the interactors of the C1-C2 region, by yeast two-hybrid analysis, we not only intend determining the ligands of the N-terminal, under different phosphorylation states, but we also hope to gain insight into the regulation of cardiac contractility by cMyBPC.     

Supervisor: Prof Hanlie Moolman-Smook