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  • Author
    Aanand Patel
  • Co-author

    Alex M. Grunfeld, Haruko Nakano, Andrea Chaney, Atsushi Nakano, Margot E. Quinlan

  • Title

    Actin assembly by Fhod3 in the cardiac sarcomere

  • Abstract

    The sarcomere, the fundamental contractile unit of a muscle cell, consists of a precisely organized lattice of actin and myosin filaments. The actin-binding protein Fhod3 is required for actin filament assembly in cardiac sarcomeres, and mutations to Fhod3 cause hypertrophic cardiomyopathy. Fhod3 belongs to a broader group of actin-binding proteins called formins, which are known for their ability to polymerize actin. However, this ability has not been observed with Fhod3 in vitro, raising the question of how Fhod3 can promote sarcomere assembly during normal development and how mutations to Fhod3 cause hypertrophic cardiomyopathy. Our recent observation that the related formin Fhod1 in fact nucleates actin, but with a preference for non-muscle actin isoforms, prompted us to revisit the question of how Fhod3 assembles actin filaments. We show that Fhod3 accelerates actin assembly in vitro. Also like other Fhod family members, Fhod3 binds tightly to the growing ends of filaments and permits, but does not accelerate, elongation. We are now combining these biochemical assays with experiments in human stem cell-derived cardiomyocytes to determine the mechanism and functional importance of Fhod3's isoform preference and slow elongation rate.

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