Barrett T, Xiao B, Dodson E J, Dodson G, Ludbrook S B, Nurmahomed K, Gamblin S J, Musacchio A, Smerdon S J, Eccleston J F
National Institute for Medical Research, London, UK.
Nature. 1997 Jan 30;385(6615):458-61. doi: 10.1038/385458a0.
Members of the Rho family of small G proteins transduce signals from plasma-membrane receptors and control cell adhesion, motility and shape by actin cytoskeleton formation. They also activate other kinase cascades. Like all other GTPases, Rho proteins act as molecular switches, with an active GTP-bound form and an inactive GDP-bound form. The active conformation is promoted by guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins (GAPs) which stimulate the intrinsic GTPase activity of small G proteins. Rho-specific GAP domains are found in a wide variety of large, multi-functional proteins. Here we report the crystal structure of an active 242-residue C-terminal fragment of human p50rhoGAP. The structure is an unusual arrangement of nine alpha-helices, the core of which includes a four-helix bundle. Residues conserved across the rhoGAP family are largely confined to one face of this bundle, which may be an interaction site for target G proteins. In particular, we propose that Arg 85 and Asn 194 are involved in binding G proteins and enhancing GTPase activity.
小G蛋白Rho家族的成员从质膜受体转导信号，并通过肌动蛋白细胞骨架的形成来控制细胞黏附、运动和形态。它们还激活其他激酶级联反应。与所有其他GTP酶一样，Rho蛋白作为分子开关，有活性的GTP结合形式和无活性的GDP结合形式。鸟嘌呤核苷酸交换因子促进活性构象，而GTP酶激活蛋白（GAPs）刺激小G蛋白的内在GTP酶活性，促进无活性状态。Rho特异性GAP结构域存在于多种大型多功能蛋白中。在此，我们报道了人p50rhoGAP的一个由242个残基组成的活性C末端片段的晶体结构。该结构是由九个α螺旋组成的不寻常排列，其核心包括一个四螺旋束。rhoGAP家族中保守的残基主要局限于该束的一个面上，这可能是与靶G蛋白的相互作用位点。特别是，我们提出Arg 85和Asn 194参与结合G蛋白并增强GTP酶活性。
