Mechanism and Function of Formins in the Control of Actin Assembly

Abstract

Formins are a widely expressed family of proteins that govern cell shape, adhesion, cytokinesis, and morphogenesis by remodeling the actin and microtubule cytoskeletons. These large multidomain proteins associate with a variety of other cellular factors and directly nucleate actin polymerization through a novel mechanism. The signature formin homology 2 (FH2) domain initiates filament assembly and remains persistently associated with the fast-growing barbed end, enabling rapid insertion of actin subunits while protecting the end from capping proteins. On the basis of structural and mechanistic work, an integrated model is presented for FH2 processive motion. The adjacent FH1 domain recruits profilin-actin complexes and accelerates filament elongation. The most predominantly expressed formins in animals and fungi are autoinhibited through intramolecular interactions and appear to be activated by Rho GTPases and additional factors. Other classes of formins lack the autoinhibitory and/or Rho-binding domains and thus are likely to be controlled by alternative mechanisms.

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

“…The FH2 domain nucleates and processively elongates actin filaments by associating with growing barbed ends and creating a biochemical environment favoring actin monomer addition (Kovar, 2006) (Figure 3b). mDia family formins are tightly regulated (Goode and Eck, 2007) by a Rho-controlled autoregulatory mechanism mediated by the interaction between their N-terminal (Dia-inhibitory, or DID) and C-terminal (Dia-autoregulatory, or DAD) domains (Alberts, 2001;Li and Higgs, 2005). Activated GTP-bound Rho proteins bind to the GTPase-binding domains and occlude DAD binding to DID, thus alleviating its inhibitory influence over the FH2 domain (Goode and Eck, 2007).…”

“…mDia family formins are tightly regulated (Goode and Eck, 2007) by a Rho-controlled autoregulatory mechanism mediated by the interaction between their N-terminal (Dia-inhibitory, or DID) and C-terminal (Dia-autoregulatory, or DAD) domains (Alberts, 2001;Li and Higgs, 2005). Activated GTP-bound Rho proteins bind to the GTPase-binding domains and occlude DAD binding to DID, thus alleviating its inhibitory influence over the FH2 domain (Goode and Eck, 2007). Newly generated actin filaments provide the underlying structures that drive changes in cell morphology to facilitate events as divergent as cell division, intracellular trafficking and chemotaxis (Chhabra and Higgs, 2007).…”

Cell biology of embryonic migration

“…The first mechanism is mediated by the Arp2/3 complex (Goley and Welch, 2006;Mullins and Pollard, 1999;Welch et al, 1997;Welch and Mullins, 2002) that interacts with the surface of the existing actin filaments to create sites of branching for new actin polymerization and ensure actin assembly into the dendritic network that drives the protrusion of lamellipodia. The second mechanism is mediated by formins (Goode and Eck, 2007;Pruyne et al, 2002;Zigmond, 2004;Zigmond et al, 1998) that drive actin assembly into parallel cross-linked bundles that serve as a structural basis for filopodia.…”

The effects of formins on the conformation of subdomain 1 in actin filaments

“…The FH2 domain is responsible for the binding to actin and for alteration of the polymerization properties of filaments. The FH1 domain can modulate this effect through interactions with profilin-actin [9][10][11]. Different formins can have other specific properties as they can depolymerise, sever or bundle filamentous actin [9,[12][13][14][15][16].…”

“…The FH1 domain can modulate this effect through interactions with profilin-actin [9][10][11]. Different formins can have other specific properties as they can depolymerise, sever or bundle filamentous actin [9,[12][13][14][15][16]. The effect of the formins on the structure of actin has been previously investigated in the case of FH2 domain of mouse Diaphanous-related protein 1 (mDia1-FH2) and it was found that the structure of the formin-bound filaments is significantly different from those polymerized in the absence of formins.…”