WASP family proteins, more than Arp2/3 activators

Abstract

Wiskott-Aldrich syndrome protein (WASP) family proteins have been extensively characterized as factors that promote the nucleation of actin through the activation of the protein complex Arp2/3. While yeast mostly have a single member of the family, mammalian cells have at least six different members, often with multiple isoforms. Members of the family are characterized by a common structure. Their N-termini are varied and are considered to confer spatial and temporal regulation of Arp2/3-activating activity, whereas their C-terminal half contains a polyproline-rich region, one or more WASP homology-2 (WH2) actin-binding domains and motifs that bind directly to Arp2/3. Recent studies, however, indicate that the yeast WASP homologue Las17 is able to nucleate actin independently of Arp2/3 through the function of novel G-actin-binding activities in its polyproline region. This allows Las17 to generate the mother filaments that are needed for subsequent Arp2/3 recruitment and activation during the actin polymerization that drives endocytic invagination in yeast. In this review, we consider how motifs within the polyproline region of Las17 support nucleation of actin filaments, and whether similar mechanisms might exist among other family members.

Keywords: Arp2/3; Las17; WH2; actin; nucleation; polyproline.

Figure 1.. Schematic diagram showing domains of WASP family proteins.

N-terminal domains depicted are in pale blue — WASP homology 1 (WH1); WAVE homology domain (WHD); WASH homology domain (WAHD) and the WHAMM membrane interaction domain (WM) or N-terminal domain (N). Other domains are: B, basic region; GBD, GTPase-binding domain; CC, coiled coil region; P, proline-rich domain; W, the WASP homology-2 (WH2) domain; C, the connecting or central domain; A, acidic domain. W, C and A together are referred to as the WCA domain. In general, the N-terminal domains are thought to confer spatiotemporal regulation on the protein, while the WCA regions at the C-terminal are required for activation of Arp2/3.

Figure 2.. Model showing possible involvement of the PPR of Las17 in actin polymerization.

(A) In the absence of Arp2/3, Las17 binds and nucleates actin via regions of the PPR region containing paired basic residues. The remainder of the PPR lies alongside the newly formed filament and promotes elongation of the filament via weak actin binding through the repeated proline tracts. The Las17 WH2 has a high affinity for actin monomers and can increase their local concentration when this would otherwise become limiting for PPR-mediated filament elongation. (B) In the presence of Arp2/3, a Las17–Arp2/3 complex is formed which binds to a mother filament and initiates branch formation. Branch elongation is enhanced by the PPR domain. W, WH2 domain; C, central or connecting domain; A, acidic domain; P, polyproline repeat motif. Actin is shown in grey and Arp2/3 is shown in blue.