Hierarchical Regulation of WASP/WAVE Proteins
Hierarchical Regulation of WASP/WAVE Proteins
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DOI：
10.1016/j.molcel.2008.10.012
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发表时间：
2008-11-07
期刊：
影响因子：
16
通讯作者：
Rosen, Michael K.
中科院分区：
文献类型：
--
作者：
Padrick, Shae B.;Cheng, Hui-Chun;Rosen, Michael K.
Wiskott-Aldrich 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 调节的流行范式通过不同的上游激活剂来引发自抑制的变构缓解。在这里，我们展示了叠加在变构上的额外调节水平：二聚化将活性 WASP 物种对 Arp2/3 复合物的亲和力提高了高达 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且明显不同的观察结果。这些包括细菌效应子 EspFu 和大量 SH3 结构域蛋白对 WASP 的激活、膜定位/聚类和组装成大型复合物对 WASP 的影响，以及不同家族成员之间的协作性。变构和二聚化以分层方式起作用，使 WASP/WAVE 蛋白能够整合不同类别的输入以产生广泛的细胞肌动蛋白反应。
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.