Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Annu Rev Biochem. 2010;79:707-35. doi: 10.1146/annurev.biochem.77.060407.135452.
The proteins of the Wiskott-Aldrich syndrome protein (WASP) family are activators of the ubiquitous actin nucleation factor, the Arp2/3 complex. WASP family proteins contain a C-terminal VCA domain that binds and activates the Arp2/3 complex in response to numerous inputs, including Rho family GTPases, phosphoinositide lipids, SH3 domain-containing proteins, kinases, and phosphatases. In the archetypal members of the family, WASP and N-WASP, these signals are integrated through two levels of regulation, an allosteric autoinhibitory interaction, in which the VCA is sequestered from the Arp2/3 complex, and dimerization/oligomerization, in which multi-VCA complexes are better activators of the Arp2/3 complex than monomers. Here, we review the structural, biochemical, and biophysical details of these mechanisms and illustrate how they work together to control WASP activity in response to multiple inputs. These regulatory principles, derived from studies of WASP and N-WASP, are likely to apply broadly across the family.
Wiskott-Aldrich 综合征蛋白（WASP）家族的蛋白质是普遍存在的肌动蛋白成核因子，即 Arp2/3 复合物的激活剂。WASP 家族蛋白含有一个 C 端 VCA 结构域，该结构域结合并激活 Arp2/3 复合物，响应多种输入，包括 Rho 家族 GTPases、磷酸肌醇脂质、含有 SH3 结构域的蛋白质、激酶和磷酸酶。在家族的典型成员 WASP 和 N-WASP 中，这些信号通过两个调节水平进行整合，即变构自动抑制相互作用，其中 VCA 与 Arp2/3 复合物隔离，以及二聚化/寡聚化，其中多 VCA 复合物比单体更能激活 Arp2/3 复合物。在这里，我们回顾了这些机制的结构、生化和生物物理细节，并说明了它们如何协同作用，以响应多种输入来控制 WASP 的活性。这些来自 WASP 和 N-WASP 研究的调节原理可能广泛适用于整个家族。
