Nucleation is defined as the formation of a stable actin polymer from its monomeric units [5] and may also be facilitated by formin. Further to nucleation formins also facilitate the processive elongation of actin filaments, exclusively at the barbed end (reviewed in [6]). All members of this family share a common Formin homology 2 domain (FH2) and all but one (Dictyostelium discoideum formin, ForC) feature a FH1 domain. The diaphanous auto-regulatory domain (DAD), diaphanous inhibitory domain (DID) and the GTPase binding domain are also commonly identified in members of the formin family, though not found in all members. Each formin functions as a homodimer that shares structural similarity to F-actin. Each of these domains are functionally important, playing crucial roles in either the translocation of the protein along the growing actin filament, addition of actin monomers to the actin filament or in the regulation of the protein. 

FH2

The FH2 domain is approximately 400 amino acids in length and binds to the barbed ends of actin filaments. Binding occurs following the dimerization of two arched FH2 domains, in a head-to-tail orientation. This produces a donut-shaped dimer held together by the interactions of the ‘lasso’ subdomain, within one of the FH2 domains, and the ‘post’ subdomain of the other FH2 domain. The linker region between these subdomains contains highly conserved residues that enable the nucleation and processive capping activity of formin. With a diameter of approximately 11nm, the donut shaped dimer easily accommodates an actin filament which is approximately 8nm wide. It has long been accepted that formins track along growing actin filaments without needing to dissociate and re-associate. Several models have been proposed to explain this movement (reviewed in [7]) with the most recent evidence suggesting the FH2 dimer will rotate according to the helical structure of F-actin [8].

FH1

The FH1 domain is proline-rich and is associated with a high level of variation amongst the formin family. It varies in length from 15 to 229 residues and in proline content from 35% to 100%. It also contains a varying number of profilin binding sites [7], as exemplified in the human formins FHOD1 and FMNL2, with FHOD1 containing 2-3 profilin binding sites and FMNL2 containing 33. Although FH1 and FH2 are found in all formins (note the earlier exception above), it remains unclear whether co-operation between the domains is essential for formin function. It is generally accepted that a more concentrated pool of profilin–actin in close proximity to the FH2 domain increases the rate of elongation and that this may be further enhanced by the delivery of actin monomers by the FH1 domain to the barbed end of the filament in the correct orientation.

DAD

Recently the DAD domain was implicated in the nucleation of actin monomers, despite not being present in all members of the formin family [9]. This domain (which lies at the C-terminal end of the molecule) was originally believed to function solely in the auto-inhibition of the protein, via its interaction with the N-terminal FH3 domain. The nucleation of actin monomers is believed to result from direct binding of the DAD domain with G-actin. This is suggested to be of particular importance in the nucleation of new filaments, the elongation of filaments in the absence of profilin and at very high concentrations of free profilin that would otherwise competitively block the FH1 domain [9].

FH3 Domain (DID and DD)

The FH3 domain lies at the N-terminal end of the protein and is the least conserved domain among the various formins. It is important in the auto-regulation of the protein, forming a surface region that is recognized by the DAD domain. It is believed that binding of DAD to the FH3 domain renders the protein inactive and unable to dimerize or bind actin filaments. This however has yet to be confirmed experimentally.