Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Department of Psychiatry and Behavioral Science, Medical University of South Carolina, Charleston, SC, USA.
Small GTPases. 2020 Jan;11(1):1-7. doi: 10.1080/21541248.2017.1361898. Epub 2018 Jan 24.
Precise trafficking events, such as those that underlie synaptic transmission and plasticity, require complex regulation. G-protein signaling plays an essential role in the regulation of membrane and protein trafficking. However, it is not well understood how small GTPases and their regulatory proteins coordinate such specific events. Our recent publication focused on a highly abundant synaptic GEF, BRAG1, whose physiologic relevance was unknown. We find that BRAG1s GEF activity is required for activity-dependent trafficking of AMPARs. Moreover, BRAG1 bidirectionally regulates synaptic transmission in a manner independent of this activity. In addition to the GEF domain, BRAG1 contains several functional domains whose roles are not yet understood but may mediate protein-protein interactions and regulatory effects necessary for its role in regulation of AMPAR trafficking. In this commentary, we explore the potential for BRAG1 to provide specificity of small GTPase signaling, coordinating activity-dependent activation of small GTPase activity with signaling and scaffolding molecules involved in trafficking through its GEF activity and other functional domains.
精确的运输事件，如突触传递和可塑性的基础，需要复杂的调节。G 蛋白信号在膜和蛋白质运输的调节中起着至关重要的作用。然而，人们并不清楚小 GTP 酶及其调节蛋白如何协调这些特定事件。我们最近的出版物集中在一种高度丰富的突触鸟苷酸交换因子 BRAG1 上，其生理相关性尚不清楚。我们发现 BRAG1 的 GEF 活性是 AMPAR 活性依赖性运输所必需的。此外，BRAG1 以一种不依赖于这种活性的方式双向调节突触传递。除了 GEF 结构域外，BRAG1 还包含几个功能结构域，其作用尚不清楚，但可能介导其在调节 AMPAR 运输中的作用所需的蛋白质-蛋白质相互作用和调节效应。在这篇评论中，我们探讨了 BRAG1 提供小 GTP 酶信号特异性的潜力，通过其 GEF 活性和其他功能结构域，协调小 GTP 酶活性的活性依赖性激活与参与运输的信号和支架分子。
