formin family of proteins cluster at the plasma membrane and initiate the nucleation of actin filaments. Formin subsequently mediates filament extension with the structural integrity of the filament bundles maintained by fascin cross-linking . The alternative model is known as the "convergent elongation model". In this model, the Arp2/3 complex, which is more commonly associated with lamellipodia formation but has been found to be critical for filopodia initiation , plays a role. Here, Arp2/3 complex nucleated branches continually develop from the actin filament network located at the leading edge of the lamellipodia. These filaments are proposed to gradually converge, forming a bundle that is secured by facsin cross-linking.
Although a consensus has yet to be reached for the mechanism of formin-mediated nucleation, it is now well-established that activated formins function as dimers and form a donut-shaped complex around terminal actin subunits, orientating themselves toward the (+) end of the actin filament or nucleus . This binding is facilitated by FH2 (formin homology 2) domains within the formin monomers. Next, each formin monomer binds and captures profilin units, which are themselves already bound to G-actin monomers. This interaction is mediated by multiple stretches of polyproline residues within the FH1 domain of formins . This domain is known to range from 15-229 residues, consist of between 35% and 100% proline residues, and contain up to 16 profilin binding sites . Profilin maintains a steady pool of actin monomers by promoting ADP to ATP nucleotide exchange on G-actin. These monomers of ATP-G-actin are then added the growing actin filament. The coupling of formin with the growing end prevents capping and allows continued growth of the filaments .
The exact mechanism of nucleation remains unclear however it is believed that all seven subunits coordinate to anchor the pointed end of the new filament at a 78° angle to the existing actin network . NPFs act to deliver actin subunits to the Arp2/3 complex at the barbed end, via binding through their WH2 domain - this serves to push the leading edge of a cell forward . It has also been suggested that each component of the complex plays specific roles, with Arp2 and Arp3 interacting with the pointed end of the daughter filament and ARPC2 and ARPC4 binding to the original filament .
This bias of Arp2/3 towards branch formation on convex curvature was proposed to represent a mechanosensing mechanism whereby detection of filament curvature alters the local cytoskeleton in order to reinforce it against the imposing forces .
Included in this group of nucleators are the Spire proteins, Cordon-bleu (Cobl), Leiomodin (Lmod-2), JMY and adenomatous polyposis coli (APC). Common to each of these proteins are repeats of the actin binding motif Wiskott-Aldrich Syndrome protein (WASp) homology 2 (WH2) domain. However, additional actin binding motifs may be present in the individual members, providing variation not their mechanisms of nucleation, but importantly, in the cellular functions they facilitate.
Animation used by permission. Source: Janet Iwasa