Crystal Structures of a Formin Homology-2 Domain Reveal a Tethered Dimer Architecture

Abstract

Formin proteins participate in a wide range of cytoskeletal processes in all eukaryotes. The defining feature of formins is a highly conserved approximately 400 residue region, the Formin Homology-2 (FH2) domain, which has recently been found to nucleate actin filaments. Here we report crystal structures of the S. cerevesiae Bni1p FH2 domain. The mostly alpha-helical FH2 domain forms a unique "tethered dimer" in which two elongated actin binding heads are tied together at either end by an unusual lasso and linker structure. Biochemical and crystallographic observations indicate that the dimer is stable but flexible, with flexibility between the two halves of the dimer conferred by the linker segments. Although each half of the dimer is competent to interact with filament ends, the intact dimer is required for actin nucleation and processive capping. The tethered dimer architecture may allow formins to stair-step on the barbed end of an elongating nascent filament.

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

“…A cardiac isoform of FHOD3 is targeted to thin actin filaments via phosphorylation of tyrosine residue preventing autophagy dependent degradation [29]. Most DCM-associated SNVs in our EWAS are clustered in a region in 3' of FHOD3 that encodes the Formin FH2 domain of the protein, which is implicated in actin polymerization [30]. A FHOD3 variant, Y1249N, has been reported in a Japanese patient with a dominant form of DCM.…”

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

“…Later, a ''screw mode'' adding consideration of torsion elastic stresses further elucidated the processive capping of formins on actin filaments by preventing torsion strain accumulation [16], which was verified subsequently by the direct observation of a rotational movement by formin mDial along the single actin filament [17]. These models combined with the information gained from crystal structures of the FH2 domain [8,12] improved our understanding of the processive progression of formins along the barbed end of actin filaments. To clarify the acceleration effect of the formin motor during actin assembly, studies so far have found that the acceleration is dependent on the number of profilin binding sites in the FH1 domain [18].…”

“…Formins promote the actin filament barbed end polymerization [5,6], which is profilin-dependent in vivo [7]. The characteristic Formin-Homology-2 (FH2) domain is a dimeric donut-shaped domain that persistently associates to the barbed end of actin filaments with de novo filament nucleation function [6,8,9]. Its NH2-terminal context is the Formin-Homology-1 (FH1) domain, a proline-rich domain that binds profilin [7,10,11].…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…Formins processively elongate filaments by creating an environment at the barbed ( þ ) end that favors monomer addition (Otomo et al, 2005). The crystal structures (Xu et al, 2004;Otomo et al, 2005) of yeast and mammalian formins revealed unique 'lasso and post'-like dimers between FH2 domains. This so-called 'tethered dimer' allows for a dynamic association with the barbed end of growing filaments.…”