Resolving the Disordered C-Terminal Tail of Cardiac Troponin T and the Impact of Cardiomyopathic Mutations

Abstract

In 1994, it was demonstrated that mutations in the genes that encode thin filament proteins were identified in causing familial hypertrophic cardiomyopathy (FHC) (1). This added to the prior knowledge that mutations in the motor protein myosin had been linked to genetic cardiomyopathy (2). Since then, many descriptions of both hypertrophic and dilated cardiomyopathy (HCM and DCM respectively) have been given. Generally, cardiomyopathies are described as a heterogenous group of diseases of the myocardium (3, 4). These diseases are often associated with either systolic or diastolic dysfunction, sometimes both. Since the 1990’s, the genetic basis of HCM and DCM is widely recognized, however, although clinically described as one disease, these cardiomyopathies are often quite variable in clinical manifestation and phenotype (3, 4). This suggests the underlying mechanisms of disease are just as variable and diverse. To better understand the mechanisms that result in disease we must not only understand the late-stage clinical phenotype but also understand the natural history of disease trajectories as well as the structure and function of not only the myofilament but also its role on the larger scale of whole heart function with the cardiovascular system. As my focus in this dissertation lies on the cardiac thin filament and the regulatory proteins that impart calcium regulation to cardiac contraction, I will examine, from a structural perspective, how a relatively short segment of one of the regulatory troponin subunits regulates cardiac thin filament activation by investigating its structure, which is known to be disordered and flexible. I hope to convince you this protein segment is not only important to cardiac thin filament regulation but is also implicated in disease as a known hotspot for cardiomyopathy causing mutations and variants of unknown significance and that by understanding its disordered structure, we can better understand the mechanism(s) by which different mutations alter this typical structure and alter intermolecular interactions thus altering cardiac thin filament regulation and thus cardiac contraction.