Effects of point mutations on alpha cardiac actin protein structural and functional properties influencing the development of cardiomyopathies
Cardiomyopathies are a family of heart diseases characterized by remodeling of the left ventricle. The molecular mechanisms of cardiomyopathy disease are not understood; specific gene mutations in cardiac myocytes have been identified. This thesis focuses on studying [alpha]-cardiac actin gene (ACTC) mutations related to the development of cardiomyopathy diseases. ACTC mutations are hypothesized to cause defective actin proteins or possibly disrupt normal protein-protein interactions, leading to a pathological state. First, the intrinsic properties of ACTC mutant proteins were characterized with a variety of biochemical assays and were shown to affect structural and functional properties of actin proteins. Studies revealed that ACTC substitutions affect nucleotide binding affinity, leading to unstable or defective actin. Second, some of the ACTC substitutions appeared to disrupt in the interactions with cardiac myosin binding protein-C (cMyBP-C), which could impair heart function. Overall this research provides evidence to support the hypothesis that ACTC mutations contribute through multiple mechanisms to a disease state heart.