RGS-CONTAINING RHOGEFS & INTERACTIONS WITH HETEROTRIMERIC & SMALL G PROTEINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 RGS-RhoGEF(RGS-RhoGEF)，包括p115、LARG和PDZRhoGf，在激活G12类异源三聚体G蛋白的G蛋白偶联受体和Rho介导的导致胞质分裂和转化的途径之间起着潜在的调节作用。这些RGS-RhoGEF的C-末端一半包含重复排列的DBL同源(DH)和Pleckstrin同源(PH)结构域，这些结构域构成了大多数Rho导向的GEF中全球环境基金活性的功能单位。RGS-RhoGEF的N-末端含有Rhogef-RGS(RgRGS)结构域，其中一些rgRGS结构域可作为GTP酶激活蛋白(GAP)作用于Ga13。这项建议的目的是确定全长p115Rhogef、其与活化的Ga13的络合物、p115Rhogef与Ga13和RhoA的三元络合物以及RGS-RhoGEF的其他家族成员的溶液结构。我们最近大量纯化了PDZRhogef，它不能作为Ga13的缺口。潜在地，PDZRho全环基金可能拥有一种不同的Ga13监管机制。因此，PDZRhogef本身及其与Ga13的络合物的溶液结构将引起人们的极大兴趣。了解G蛋白调控p115Rhogef及其同系物的分子基础将有助于我们深入了解这一特定的调控途径，并加深我们对G蛋白信号转导一般机制的基本理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. RGS-containing RhoGEFs (RGS-RhoGEFs), including p115RhoGEF, LARG, and PDZRhoGEF, function as potential regulatory links between G protein coupled receptors that activate the G12 class of heterotrimeric G proteins and Rho-mediated pathways that lead to cytokinesis and transformation. The C-terminal halves of these RGS-RhoGEFs contain tandemly arranged Dbl homology (DH) and pleckstrin homology (PH) domains that constitute the functional unit of GEF activity in most Rho-directed GEFs. The N-terminal portions of the RGS-RhoGEFs possess RhoGEF-RGS (rgRGS) domains, some of the rgRGS domains function as GTPase activating proteins (GAPs) for Ga13. The purpose of this proposal was to determine the solution structures of the full length p115RhoGEF, its complex with activated Ga13, as well as the ternary complex of p115RhoGEF with Ga13 and RhoAas well as other family members of the RGS-RhoGEFs. We have recently purified, in large quantity, PDZRhoGEF, which does not function as a GAP for Ga13. Potentially, PDZRhoGEF could possess a different regulatory mechanism for Ga13. Hence, the solution structures of PDZRhoGEF alone, and its complex with Ga13 would be of great interest. Understanding the molecular basis by which p115RhoGEF and its homologs are regulated by G proteins should provide insight into this specific pathway for regulation as well as increase our fundamental understanding of general mechanisms of signaling by G proteins.