RhoGTP酶是一个高度保守的G蛋白家族,可调节许多细胞过程,包括细胞骨架组织,迁移,和扩散。20个规范的RhoGTP酶受85个鸟嘌呤核苷酸交换因子(GEF)调节,其中最大的家族是71个弥漫性B细胞淋巴瘤(Dbl)GEF。DblGEF通过高度保守的Dbl同源结构域促进GTP酶活性。全球环境基金活动的特殊性,因此GTP酶活性,在于GEF本身的监管和结构。DblGEF包含通过控制亚细胞定位来调节GEF活性的各种附属结构域,蛋白质相互作用,通常是自动抑制。本文重点介绍了两种磷脂酰肌醇(3,4,5)-三磷酸(PI(3,4,5)P3)依赖性Rac交换剂(P-Rex),特别是P-Rex1自抑制和协同激活的结构基础。首先,我们讨论了强调P-Rex催化和磷酸肌醇结合活性保守性的结构。然后,我们探索了在揭示P-Rex1自抑制的结构基础方面的最新突破,并详细介绍了所提出的PI(3,4,5)P3和Gβγ如何在膜上协同激活P-Rex1的最小两步模型。此外,我们讨论了磷酸化和P-Rex2-PTEN共抑制复合物形成提供的P-Rex调节的进一步层,尽管这些机制仍未完全理解。最后,我们利用现有数据来推断P-Rex2中的癌症相关突变如何使自身抑制不稳定并逃避PTEN共抑制复合物的形成,导致P-Rex2GEF活性增加并驱动癌症进展和转移。
Rho
GTPases are a family of highly conserved G proteins that regulate numerous cellular processes, including cytoskeleton organisation, migration, and proliferation. The 20 canonical Rho
GTPases are regulated by ∼85 guanine nucleotide exchange factors (GEFs), with the largest family being the 71 Diffuse B-cell Lymphoma (Dbl) GEFs. Dbl GEFs promote GTPase activity through the highly conserved Dbl homology domain. The specificity of GEF activity, and consequently GTPase activity, lies in the regulation and structures of the GEFs themselves. Dbl GEFs contain various accessory domains that regulate GEF activity by controlling subcellular localisation, protein interactions, and often autoinhibition. This review focuses on the two phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3)-dependent Rac exchangers (P-Rex), particularly the structural basis of P-Rex1 autoinhibition and synergistic activation. First, we discuss structures that highlight the conservation of P-Rex catalytic and phosphoinositide binding activities. We then explore recent breakthroughs in uncovering the structural basis for P-Rex1 autoinhibition and detail the proposed minimal two-step model of how PI(3,4,5)P3 and Gβγ synergistically activate P-Rex1 at the membrane. Additionally, we discuss the further layers of P-Rex regulation provided by phosphorylation and P-Rex2-PTEN coinhibitory complex formation, although these mechanisms remain incompletely understood. Finally, we leverage the available data to infer how cancer-associated mutations in P-Rex2 destabilise autoinhibition and evade PTEN coinhibitory complex formation, leading to increased P-Rex2 GEF activity and driving cancer progression and metastasis.