A nemaline myopathy-linked point mutation destabilizes the second actin binding site of tropomodulin family proteins

Abstract

Proper function of striated muscle sarcomeres depends on strict regulation of thin filament lengths. Leiomodin (Lmod) and tropomodulin (Tmod), homologous proteins both with an affinity for actin and tropomyosin, bind to the pointed end of thin filaments, altering actin polymerization dynamics and controlling thin filament lengths. Several mutations in the skeletal isoform of Lmod (Lmod3) have been linked to nemaline myopathy, a disease characterized by aberrant sarcomere assembly, hypotonia, and severe muscle weakness ultimately leading to death.