REGULATION OF THE ACTIN FILAMENT POINTED END DYNAMICS IN HEALTH AND DISEASE

Washington State University, Pullman WA

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Abstract

In striated muscles, actin thin filament architecture is critical for efficient contractile activity, and alterations in thin filament integrity are linked to severe and often lethal skeletal and cardiac muscle diseases. Our long-term goal is to identify the components and molecular mechanisms regulating actin architecture in striated muscle during normal development and disease. In this project, we will evaluate how actin-binding proteins of the tropomodulin family (e.g. leiomodin, or Lmod, and tropomoduin, or Tmod) affect the formation and then the structure of the thin filament. We will test our recently proposed molecular mechanism for the Lmod/Tmod-dependent regulation of the pointed end of the thin filaments. We will also study the structural and functional consequences of Lmod binding to sides of the already formed thin filaments. Finally, we will establish mechanisms of regulation of Lmod functions. We propose three aims to identify underlying molecular mechanisms of the full spectrum of Lmod functions: (1) to decipher the role of Lmod in the maintenance of proper thin filament lengths via pointed end regulation; (2) to establish the role of Lmod’s actin-binding sites in thin filament activation; (3) to test the hypothesis that Lmod functions are regulated by Ca2+. Our data will provide a comprehensive identification of critical components of the regulatory mechanisms underlying thin filament assembly and maintenance in health and disease.