Biology Reference
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the Arp subunits relative to each other in an identical way to that observed
in actin filaments thus providing the necessary actin dimer to trigger
polymerization (Robinson et al., 2001).
According to the dendritic nucleation model, WASp proteins activate Arp2/
3 complex to initiate the formation of 708 actin branches at the leading edge of
migrating cells. Currently, models predict that the Arp2/3 complex binds to
the mother filament and is simultaneously activated by WASp/Scar proteins at
the plasma membrane. The complex presumably then becomes incorporated
into the branch point with the two Arps forming the first subunits of the
branch (Volkmann et al., 2001). Exactly which subunits contact the filament is
still subject to debate. While the crystal structure of the complex suggests p34-
Arc and p40-Arc are the leading candidates (Robinson et al., 2001), recent
work using recombinant Arp2/3 complex reveals that p40-Arc is not required
and that the anchoring subunits may be p34-Arc and p20-Arc (Gournier et al.,
2001).
So far we have discussed howWASp family proteins may activate the Arp2/3
complex, but WASp family proteins are also subject to tight regulation. Since
there are five WASp-related proteins in mammals, the different mechanisms of
activation might provide specificity for the context and type of cellular process
(such as lamellipodia versus phagosomes, for example). WASp and N-WASp
are apparently regulated by autoinhibition (Figure 8.2, Miki, H. et al., 1998).
In their native states, WASp and N-WASp are held in an auto-inhibited
confirmation in which the WA region is prevented from activating/binding the
Arp2/3 complex by interaction with its own C-terminal region (Figure 8.2).
This inactive confirmation is released on binding of the GBD with activated
Cdc42 and perhaps PIP
2
, allowing activation of the Arp2/3 complex and new
filament nucleation (Rohatgi et al., 2000). WASp and N-WASp can also bind
to the SH3 domains of adaptor proteins such as Grb2 via their proline-rich
sequences providing yet another potential route to activation (Carlier et al.,
2000). Another adapter protein WISH (WASp interacting SH3 protein) also
binds both WASp and N-WASp via its SH3 domain leading to increased N-
WASp activation of Arp2/3
complex-mediated actin polymerization
(Fukuoka et al., 2001).
While the mechanisms of WASp/N-WASp activation have begun to be
understood activation of Scar proteins have, until this year, remained a
mystery. Previous reports have suggested that they can be regulated by the
GTPase Rac (Miki et al., 1998b). However as Scars lack the GBD found in
WASp/N-WASp the mechanism was unclear. Now Eden and co-workers
(Eden et al., 2002) have shown that Scar1/WAVE1 exists as a heteropenta-
meric complex consisting of the proteins PIR121, Nap124, Abi2 and
HSPC300 (Figure 8.2) which is inactive in vitro. Excitingly, Rac1 can relieve
this trans-inhibition by binding to the PIR-21-Nap124-Abi2 sub-complex
resulting in release of the Scar1-HSPC300 complex that is able to stimulate
