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Understanding the molecular mechanisms of cardiomyopathy-causing mutations in sarcomeric proteins [electronic resource]

Heart disease is one of the leading causes of morbidity and mortality in the developed world. As such, significant amount of resources and energy are funneled into developing treatments and therapeutics. While genetically caused cardiovascular diseases manifest at the tissue level, the fundamental mechanism that triggers the secondary effects and tissue remodeling generally occurs at the protein level. It is therefore critical to understand the molecular changes on the basic biochemical and biophysical level and connect these to the cellular and developmental disease processes. One such cardiovascular disorder is hypertrophic cardiomyopathy or HCM, which has been estimated to affect approximately 1 in 500 individuals. It disproportionately affects young adults and is the leading cause of sudden cardiac death. Since the first case of genetically linked HCM was identified in the early 1990s, a significant amount of work has been done to understand the molecular mechanism of the disease. Mutations have been identified in the proteins comprising the contractile apparatus of the muscle, the sarcomere. One such protein is [beta]-cardiac myosin, which has been recognized as a significant culprit of genetically linked HCM (~30-50%). Many studies have been performed to understand how single point mutations can alter the enzymatic and mechanical properties of this motor protein, but there is no clear consensus about the molecular mechanism. This has been due mainly to the lack of available human [beta]-cardiac myosin and the use of non-human and non-[beta]-cardiac myosin. Non-human and non-[beta]-cardiac myosin from common animal models differ by >30 residues, and as clearly evident from the disease and from previous studies on myosin, a single amino acids mutation can significantly alter and disrupt myosin function. During my thesis work, I have performed the first biochemical and biophysical work in the field looking at cardiomyopathy mutations using human [beta]-cardiac myosin. I have shown that HCM-causing [beta]-cardiac myosin mutations result in a gain of function, increasing the power or work output of the myosin. I have also examined HCM-causing mutations in troponin T, a component of the thin filament regulatory unit, using human [beta]-cardiac myosin. In the muscle, the interaction of myosin and actin is regulated by calcium through the thin filament proteins, namely the troponin complex and tropomyosin. HCM-causing mutations in troponin T increase calcium sensitivity or the number of force-producing heads that can interact with actin, thereby also increasing force or power output in the muscle. My work not only sheds light on fundamental properties of thick and thin filament function in the human sarcomere and presents the first studies of HCM-causing mutants in a human background, it also establishes a new approach to the problem of cardiomyopathy that will be critical in truly understanding and targeting the disease.