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
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.