IQGAP1 Structure and Function

描述（由申请人提供）：IQGAP 1是一种190 kD的胞质蛋白支架，具有几个蛋白质-蛋白质相互作用结构域。最近的研究结果将IQGAP 1与许多蛋白质联系起来，包括生长因子受体、MAP激酶信号传导组分和细胞连接蛋白。虽然细节还不清楚，但通过不同的相互作用，IQGAP 1在许多过程中发挥重要作用，包括细胞极性的定义，定向细胞迁移和细胞侵袭。越来越多的间接证据表明IQGAP 1参与了致癌作用，并且IQGAP 1在几种不同的肿瘤中过表达。在其他有趣的观察中，IQGAP 1的过表达已被证明会破坏基于钙粘蛋白的细胞-细胞连接，并以Rac 1/Cdc 42依赖性方式增加细胞运动性和侵袭性。目前，IQGAP 1及其蛋白质-蛋白质相互作用的结构信息很少。然而，一些观察结果表明IQGAP 1不是一个被动的支架，只是收集信号成分。首先，IQGAP 1的寡聚化是正常功能所必需的。其次，IQGAP 1是Rho家族GTP酶Rac 1和Cdc 42的新型效应物，活化Cdc 42的结合增强二聚体形成并调节IQGAP 1 C末端介导的相互作用。第三，在IQGAP 1 GAP相关结构域（GRD）内引入17个残基的突变赋予了“组成型活性”表型; IQGAP 1分子的行为就像与活性Cdc 42结合一样。17个残基插入位于GRD的表面上，如果结合模式与Ras？RasGAP交互。最后，IQGAP 1氨基末端残基反式抑制IQGAP 1 C末端和N-WASP之间的相互作用。基于这些和其他观察结果，我们认为，通过不同的分子间和分子内相互作用，IQGAP 1暴露和隐藏其功能调节所必需的结合决定簇。该提案的重点是阐明IQGAP 1的三级结构和IQGAP 1与结合伴侣相互作用的结构要求。

DESCRIPTION (provided by applicant): IQGAP1 is a 190kD cytosolic protein scaffold that possesses several protein-protein interaction domains. The results of recent research link IQGAP1 to numerous proteins including growth factor receptors, MAP kinase signaling components, and cell junction proteins. Although the details are not well understood, through diverse interactions IQGAP1 has an important role in numerous processes including the definition of cell polarity, directed cell migration, and cell invasion. There is a growing body of circumstantial evidence that IQGAP1 is involved in carcinogenesis, and IQGAP1 is overexpressed in several different neoplasms. Among other intriguing observations, over-expression of IQGAP1 has been shown to destabilize cadherin-based cell-cell junctions and increase cell motility and invasiveness in a Rac1/Cdc42-dependent manner. Currently, there is very little structural information for IQGAP1 and its protein-protein interactions. However, several observations imply that IQGAP1 is not a passive scaffold that merely collects signaling components. First, the oligomerization of IQGAP1 is required for normal function. Second, IQGAP1 is a novel effector of the Rho-family GTPases Rac1 and Cdc42 and binding of activated Cdc42 enhances dimer formation and modulates interactions mediated by the IQGAP1 C-terminus. Third, a mutation that introduces 17 residues within the IQGAP1 GAP-related domain (GRD) confers a "constitutively-active" phenotype; IQGAP1 molecules that behave as though bound to active Cdc42. The 17 residue insertion is located on the surface of the GRD that would bind GTPases if the mode of binding is similar to the Ras?RasGAP interaction. Lastly, IQGAP1 amino terminal residues inhibit in trans the interaction between the IQGAP1 C-terminus and N-WASP. Based on these and other observations, we believe that through diverse inter- and intramolecular interactions, IQGAP1 exposes and conceals binding determinants necessary for the regulation of its functions. The focus of this proposal is to elucidate the IQGAP1 tertiary structure and the structural requirements for IQGAP1's interactions with binding partners.