PDF(Pubmed)
Abstract：
Transmembrane signaling is a critical process by which changes in the extracellular environment are relayed to intracellular systems that induce changes in homeostasis. One family of intracellular systems are the guanine nucleotide exchange factors (GEFs), which catalyze the exchange of GTP for GDP bound to inactive guanine nucleotide binding proteins (G proteins). The resulting active G proteins then interact with downstream targets that control cell proliferation, growth, shape, migration, adhesion, and transcription. Dysregulation of any of these processes is a hallmark of cancer. The Dbl family of GEFs activates Rho family G proteins, which, in turn, alter the actin cytoskeleton and promote gene transcription. Although they have a common catalytic mechanism exercised by their highly conserved Dbl homology (DH) domains, Dbl GEFs are regulated in diverse ways, often involving the release of autoinhibition imposed by accessory domains. Among these domains, the pleckstrin homology (PH) domain is the most commonly observed and found immediately C-terminal to the DH domain. The domain has been associated with both positive and negative regulation. Recently, some atomic structures of Dbl GEFs have been determined that reemphasize the complex and central role that the PH domain can play in orchestrating regulation of the DH domain. Here, we discuss these newer structures, put them into context by cataloging the various ways that PH domains are known to contribute to signaling across the Dbl family, and discuss how the PH domain might be exploited to achieve selective inhibition of Dbl family RhoGEFs by small-molecule therapeutics. SIGNIFICANCE STATEMENT: Dysregulation via overexpression or mutation of Dbl family Rho guanine nucleotide exchange factors (GEFs) contributes to cancer and neurodegeneration. Targeting the Dbl homology catalytic domain by small-molecule therapeutics has been challenging due to its high conservation and the lack of a discrete binding pocket. By evaluating some new autoinhibitory mechanisms in the Dbl family, we demonstrate the great diversity of roles played by the regulatory domains, in particular the PH domain, and how this holds tremendous potential for the development of selective therapeutics that modulate GEF activity.
摘要：
跨膜信号传导是细胞外环境的变化被传递到诱导稳态变化的细胞内系统的关键过程。一种常见的细胞内系统涉及鸟嘌呤核苷酸交换因子（GEF），催化GTP交换与无活性鸟嘌呤核苷酸结合蛋白（G蛋白）结合的GDP。然后，产生的活性G蛋白与控制细胞增殖的下游靶标相互作用，增长,形状,迁移,附着力,和转录。任何这些过程的失调都是癌症的标志。GEF的Dbl家族激活Rho家族G蛋白,进而改变肌动蛋白细胞骨架并促进基因转录。尽管它们具有通过其保守的Dbl同源（DH）结构域行使的共同催化机理，DblGEF以非常不同的方式进行调节。通常,这种调节涉及附属结构域施加的自抑制的释放。在这些领域中，pleckstrin同源性（PH）结构域是最保守的，并且几乎总是在DH结构域的C端立即发现。该域与正调节和负调节都相关。最近,已经确定了DblGEF的一些原子结构，这些结构再次强调了PH结构域在协调DH结构域调节中可以发挥的复杂和核心作用。在这里我们讨论这些新的结构，通过分类已知PH结构域有助于Dbl家族信号传导的各种方式，将它们放入上下文中，并讨论如何利用PH通过小分子疗法实现对该蛋白质家族的选择性抑制。意义陈述通过Dbl家族RhoGEF的过表达或突变引起的失调促成疾病。通过小分子治疗剂靶向Dbl同源性(DH)催化结构域由于其高度保守性和缺乏离散结合口袋而具有挑战性。通过评估Dbl家族中一些新的自动抑制机制，我们展示了监管领域所扮演的角色的多样性，特别是PH域，以及这如何具有开发调节GEF活性的选择性疗法的巨大潜力。
