Biology Reference
In-Depth Information
Figure 8.2 Activation of WASp/N-WASp and Scar/WAVE proteins WASp and N-WASp
are folded such that the tail (grey) interacts with a Cdc42 GTPase binding domain (GBD,
white box). Activation occurs when GTP-bound Cdc42 and possibly also membrane
polyphosphoinositides interact with the GBD and a nearby basic patch (black) and open it
up to cause activation and interaction with the Arp2/3 complex (gradient shading). Scars/
WAVES lack a GBD and do not show this autoinhibition in vitro. Instead, bovine brain
Scars have been reported to bind to cytoplasmic inhibitors, including the Rac-binding
protein p140-Sra and the Nck-interacting protein Nck-AP1. Scar1 also binds to the small
protein HSPC300, but the consequence of this interaction has not been reported. The
model for Scar1 activation in response to signalling is that activated Rac GTPase binds to
p140-Sra and causes it and Nck-AP to fall off Scar1, leaving the active Scar1-HSPC300
complex to interact with and activate the Arp2/3 complex (Eden et al., 2002). This model is
attractive but has not yet been tested in vivo
But how do these proteins activate Arp2/3 complex and stimulate actin
polymerization? At present it is believed that WASp family proteins bind to
actin monomers, which subsequently are passed on to the Arp2/3 complex.
The two Arp subunits interact with the pointed end of the actin monomer
thus allowing polymerization in the direction of the free barbed end - with
Arp2 and Arp3 forming the first two subunits of the filament (Mullins et al.,
1997). Recent biochemical evidence supports this hypothesis, as recombinant
Arp2/3 complex that lacks Arp3 is unable to nucleate actin filaments
(Gournier et al., 2001). The recently published crystal structure of the Arp2/
3 complex may explain why activation by WASp proteins is required for
e
cient activation of Arp2/3 mediated actin polymerization (Dayel et al.,
2001). Although the two Arps lie in an approximate head-to-tail fashion
(like subunits of an actin filament) they are rotated 1808 relative to each
other (Robinson et al., 2001). It is believed WASp family proteins bind the
Arp2/3 complex promoting a conformational change resulting in a
translation of Arp2 relative to Arp3. Such a translation would position
