Leiomodin 2 functions as an actin polymerase enabling processive pointed-end elongation of actin filaments, an activity greatly reduced by human dilated cardiomyopathy-associated mutations.
The cardiac protein Leiomodin 2 acts as an actin filament polymerase at the pointed end, and its impairment by mutations provides a potential mechanism for dilated cardiomyopathy.
The actin cytoskeleton drives essential processes like cell migration and muscle contraction. While barbed-end polymerization is well-established, pointed-end elongation was long considered impossible in vivo. Here, we demonstrate that Leiomodin 2 (Lmod2), which localizes to thin-filament pointed ends in striated muscle cells, functions as an actin polymerase for pointed-end elongation. Single-molecule and single-filament imaging reveal that Lmod2 remains processively bound to pointed ends in vitro, enabling elongation even in the presence of high profilin concentrations found in the cytoplasm that otherwise would cause depolymerization of free pointed ends. Kinetic analysis indicates that Lmod2-mediated elongation proceeds through a linked two-step mechanism, in which monomer addition is followed by a first-order transition at the Lmod2-bound pointed end that limits elongation at high actin concentrations. Lmod2’s activity also persists in the presence of tropomyosin, underscoring its physiological relevance. Both processivity and elongation rate of Lmod2 are dependent on its WH2 domain. Remarkably, human dilated cardiomyopathy-associated mutations in Lmod2 greatly reduce Lmod2’s pointed-end elongation activity, providing a potential mechanism for disease progression and supporting a role for Lmod2-mediated polymerization in the formation and maintenance of muscle sarcomeres. This study identifies the cardiac protein Leiomodin 2 as an actin filament polymerase that enables growth from filament pointed ends, revealing how muscle actin filament length is controlled and how Lmod2 mutations may cause dilated cardiomyopathy.
Biswas et al. (Mon,) conducted a other in Dilated cardiomyopathy. Leiomodin 2 (Lmod2) was evaluated on Pointed-end elongation of actin filaments. Leiomodin 2 functions as an actin polymerase enabling processive pointed-end elongation of actin filaments, an activity greatly reduced by human dilated cardiomyopathy-associated mutations.