Padrick Shae B, Cheng Hui-Chun, Ismail Ayman M, Panchal Sanjay C, Doolittle Lynda K, Kim Soyeon, Skehan Brian M, Umetani Junko, Brautigam Chad A, Leong John M, Rosen Michael K
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell. 2008 Nov 7;32(3):426-38. doi: 10.1016/j.molcel.2008.10.012.
Members of the Wiskott-Aldrich syndrome protein (WASP) family control actin dynamics in eukaryotic cells by stimulating the actin nucleating activity of the Arp2/3 complex. The prevailing paradigm for WASP regulation invokes allosteric relief of autoinhibition by diverse upstream activators. Here we demonstrate an additional level of regulation that is superimposed upon allostery: dimerization increases the affinity of active WASP species for Arp2/3 complex by up to 180-fold, greatly enhancing actin assembly by this system. This finding explains a large and apparently disparate set of observations under a common mechanistic framework. These include WASP activation by the bacterial effector EspFu and a large number of SH3 domain proteins, the effects on WASP of membrane localization/clustering and assembly into large complexes, and cooperativity between different family members. Allostery and dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses.
威斯科特-奥尔德里奇综合征蛋白（WASP）家族的成员通过刺激Arp2/3复合物的肌动蛋白成核活性来控制真核细胞中的肌动蛋白动力学。WASP调节的主流模式是由多种上游激活剂引起的自抑制的变构解除。在这里，我们展示了一种叠加在变构之上的额外调节水平：二聚化使活性WASP物种对Arp2/3复合物的亲和力增加高达180倍，极大地增强了该系统的肌动蛋白组装。这一发现解释了在一个共同的机制框架下大量明显不同的观察结果。这些包括细菌效应器EspFu和大量SH3结构域蛋白对WASP的激活，膜定位/聚集以及组装成大复合物对WASP的影响，以及不同家族成员之间的协同作用。变构和二聚化以分级方式起作用，使WASP/WAVE蛋白能够整合不同类型的输入，以产生广泛的细胞肌动蛋白反应。
