Papayannopoulos Venizelos, Co Carl, Prehoda Kenneth E, Snapper Scott, Taunton Jack, Lim Wendell A
Department of Cellular and Molecular Pharmacology and Program in Biological Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Mol Cell. 2005 Jan 21;17(2):181-91. doi: 10.1016/j.molcel.2004.11.054.
Phosphatidylinositol 4,5-bisphosphate (PIP(2)) activates the actin regulatory protein N-WASP by binding to a short polybasic region involved in N-WASP autoinhibition. Here, we show that unlike canonical lipid binding modules, such as PH domains, this polybasic motif binds PIP(2) in a multivalent, cooperative manner. As a result, PIP(2) activation of N-WASP-mediated actin polymerization in vitro and in extracts is ultrasensitive: above a certain threshold, N-WASP responds in a switch-like manner to a small increase in the density of PIP(2) (Hill coefficient n(H) = approximately 20). We show that the sharpness of the PIP(2) activation threshold can be tuned by varying the length of the polybasic motif. This sharp activation threshold may help suppress N-WASP activation by quiescent PIP(2) levels yet leave it poised for activation upon subtle, signaling-induced perturbations in PIP(2) distribution.
磷脂酰肌醇4,5 - 二磷酸（PIP(2)）通过与参与N-WASP自身抑制的短多碱性区域结合来激活肌动蛋白调节蛋白N-WASP。在此，我们表明，与典型的脂质结合模块（如PH结构域）不同，这种多碱性基序以多价协同方式结合PIP(2)。因此，PIP(2)在体外和提取物中对N-WASP介导的肌动蛋白聚合的激活是超敏感的：高于某个阈值时，N-WASP以类似开关的方式对PIP(2)密度的小幅增加做出反应（希尔系数n(H)约为20）。我们表明，可以通过改变多碱性基序的长度来调节PIP(2)激活阈值的锐度。这种尖锐的激活阈值可能有助于抑制静止PIP(2)水平对N-WASP的激活，但使其在PIP(2)分布发生细微的信号诱导扰动时随时准备被激活。
