Formin conformations during processive actin elongation

Abstract

Formins are a class of actin binding proteins that regulate the elongation and nucleation of actin filaments and they are key to maintaining cellular morphology. The mammalian formin‐like 3 (FMNL3) protein is essential for the formation of filopodia, projections of the plasma membrane that enable cell motility. Formins contain a highly conserved formin homology 2 (FH2) domain that dimerizes through interactions of the lasso and post subdomains. These dimers bind to actin filament barbed ends to mediate elongation and prevent inhibition of filament growth by capping proteins, thereby ensuring the formation of long, linear actin filaments. The FH2 dimer is able to remain associated with the growing end of the filament during elongation through the flexibility of linker regions that connect the FH2 subunits. A previous structural study of the yeast formin Bni1p FH2 domain was found to form a complex with three adjacent actin subunits, supporting a simple stepping model of formin‐mediated actin polymerization. The X‐ray crystal structure of the FMNL3 FH2 domain was solved in complex with monomeric actin. In this structure, the FH2 dimer forms a symmetric and stable complex with only two actin monomers through primary interactions between the knob and coiled‐coil FH2 subdomains and actin. These recent findings support the existence of an additional step in the formin‐mediated processive elongation mechanism. The Pingry School 2014‐2015 SMART team has created a model to further examine the structure and function of formin FH2 domains in complex with actin.