Research Project
10292264
Project Summary Project Title: Myopalladin?s role in cardiac muscle function and disease Decades of research have provided fundamental insight into the human heart?s structure and function. Yet, most cardiac malformations remain a mystery as scientists and clinicians continue to examine how inherited mutations and aging affect the normal biological functions of proteins associated with cardiac dysfunction. Recently, mutations in the muscle protein myopalladin have been linked to the pathogenesis of three of the four major types of cardiomyopathy. Myopalladin is thought to be involved in regulating the organization of sarcomere structure, however insufficient knowledge of myopalladin?s interactions with other key molecules in the sarcomere has hampered development of new therapies for cardiomyopathies and other debilitating muscle diseases. Mutations in myopalladin cause diverse cardiomyopathic phenotypes that are poorly understood; therefore, our goal is to uncover the molecular mechanisms and discover how sarcomere thin filament assembly occurs. Myopalladin and palladin belong to a family of closely related immunoglobulin (Ig)-domain-containing proteins that have essential, but uncharacterized roles in organizing the actin cytoskeleton. Previous work in the Beck lab revealed that palladin binds directly to actin and increases both the rate of actin polymerization and the stability of actin filaments. Our more recent results indicate that myopalladin also binds and bundles filamentous actin, however myopalladin reduced actin polymerization and strongly inhibits depolymerization. The fact that a number of mutations in myopalladin are located within the analogous actin-binding region suggests that a disruption in actin regulation may occur in cardiomyopathy. The objective of this application is to provide new insights into the still largely elusive role of myopalladin in cardiac structure, function, and disease. We will investigate the functional properties of myopalladin by employing multidisciplinary studies that integrate structural and functional analysis of isolated proteins with characterization of actin assembly and sarcomere structure in cultured and live cells. We will test our hypothesis that myopalladin promotes thin filament actin elongation by examining interactions critical for this regulation that may also be disrupted by the cardiomyopathy-associated mutations recently identified. Such studies will be a significant advance in our understanding of familial cardiomyopathy and may motivate the development of new strategies to detect and treat cardiac disease.
