Key result
Leiomodin 2 acts as the first eukaryotic polymerase driving processive pointed-end actin filament elongation.
Why the study?
While barbed-end actin polymerization is well-established, pointed-end elongation was long considered impossible in vivo.
The identification of Lmod2 as the first eukaryotic processive actin polymerase at the pointed end provides a novel mechanism for sarcomere maintenance and explains the molecular basis of LMOD2 mutations in severe pediatric dilated cardiomyopathy.
May inform LMOD2 cardiomyopathy mechanisms; challenges consensus that pointed-end actin elongation is impossible in eukaryotes.
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 (PEs) in striated muscle cells, functions as the first identified eukaryotic processive actin polymerase. Single-molecule and single-filament imaging reveal that Lmod2 stably associates with PEs in vitro , enabling elongation even in the presence of high profilin concentrations found in the cytoplasm that otherwise would cause depolymerization of free PEs. We find that both processivity and elongation rate of Lmod are dependent on its WH2 domain. Remarkably, human dilated cardiomyopathy-associated mutations in Lmod2 greatly reduce Lmod2’s PE elongation activity, providing a potential mechanism for disease progression, underscoring the essential role of its actin polymerase activity in formation and maintenance of muscle sarcomeres.
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Biswas et al. (2026) studied this question. Leiomodin 2 (Lmod2) vs. Free pointed ends (without Lmod2) was evaluated on Actin filament pointed-end elongation rate and processivity. Leiomodin 2 functions as the first identified eukaryotic processive actin polymerase that directly elongates actin filaments from their pointed ends in vitro.
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