The Effect of Intermolecular Interactions in the Elongation Rates of Actin Filament by Formins

Abstract

Formins are large proteins (120–220 kDa) with multiple domains that regulate the elongation of actin filaments. The FH2 domains (~400 amino acids) form the core structure of formins and bind the growing barbed end of actin filaments, which slow the rate of barbed end elongation depending on the formin bound to it. We use multiscale simulation techniques to investigate the interactions of three formins FH2 domains (fission yeast Cdc12, budding yeast Bni1p, mouse mDia1) and the barbed end of the actin filament to understand these formins polymerize actin at different rates. The simulations demonstrated that the elongation rates of formins can be affected by the dissimilarities in their structures and intermolecular interactions with the barbed end. In addition, we identified critical regions of formins that are significant for regulating the configuration of the barbed end of the filament. The interactions between FH2 domains and actin filament in these regions differ among the formins (such as salt bridge formation), which can contribute to variation in modulating the barbed‐end configuration. The coarse‐grained simulations predicted that the FH2 domains have different stabilities at the barbed‐end, thus they have different degrees of steric interference to the addition of actin monomer. This work can help to resolve the underlying molecular mechanisms used by different formins to assemble actin networks.