Structural basis of rapid actin dynamics in the evolutionarily divergent Leishmania parasite

AbstractActin polymerization generates forces for cellular processes throughout the eukaryotic kingdom, but our understanding of the ‘ancient’ actin turnover machineries is limited. We show that, despite > 1 billion years of evolution, pathogenicLeishmania majorparasite and mammalian actins share the same overall fold and co-polymerize with each other. Interestingly,Leishmaniaharbors a simple actin-regulatory machinery that lacks cofilin ‘cofactors’, which accelerate filament disassembly in higher eukaryotes. By applying single-filament biochemistry we discovered that, compared to mammalian proteins,Leishmaniaactin filaments depolymerize more rapidly from both ends, and are severed > 100-fold more efficiently by cofilin. Our high-resolution cryo-EM structures ofLeishmaniaADP-, ADP-Pi- and cofilin-actin filaments identify specific features at actin subunit interfaces and cofilin-actin interactions that explain the unusually rapid dynamics of parasite actin filaments. Our findings reveal how divergent parasites achieve rapid actin dynamics using a remarkably simple set of actin-binding proteins, and elucidate evolution of the actin cytoskeleton.