Regulatory mechanism dictating GPSM3 selectivity toward G protein-coupled receptor complex

背景：G蛋白偶联受体(GPCRs)是一种大的变构机器，它们动态结合细胞外和细胞内的配体或蛋白质形成复合体，传播构象受限的细胞信号。这种互换变构系统是GPCR信号的多维性和异质性的基础。GPCRs作为异源三聚体蛋白(G)的催化激活剂，通过GTP交换G亚基上的结合GDP。这种鸟嘌呤核苷酸交换因子的活性是G蛋白周期的初始步骤，并决定了各种细胞内信号通路的启动。调节蛋白和辅助蛋白通过控制信号的幅度和持续时间来微调细胞内的信号转导，或者充当G蛋白非依赖信号的支架。最新的信号调控模式之一是发现非活性GI/O亚基与GoLoco(也称为GPR)基序蛋白之间的关联，这种关联排除了G·GDP/G非活性异三聚体的改造。 这项研究计划的长期目标是致力于GPR基序蛋白中最小的成员之一的特性，称为GPSM3(G蛋白信号调节器类型3)。我们以前的工作表明，GPSM3在造血细胞中显著表达，在炎症性疾病的发生中起着重要作用。最近的一项突破表明，Gi/o-GPSM3复合体直接与GPCR偶联，可以作为一种新的信号平台来取代传统的G。这些工作为研究新的支架蛋白打开了大门，这些支架蛋白可以组织控制GPSM3介导的GPCR功能的特定信号复合体。 今后五年，我们将围绕具体目标，回答以下问题： 目标-1：GPSM3对GPCRs的选择性是什么？ 目的-2：什么大分子组织控制着GPSM3的选择性和特异性？ 综上所述，这些研究将为更好地理解一种新型的GPCR调节器奠定基础。我们相信，这一全球功能方法将导致一个信号网络的构建，这将揭示一种具有广泛意义的新的信号传播和调控机制。所提供的计划将提供一个很好的机会，利用创新工具的组合来培训HQP，并将对参与HQP的人员进行奖励。

Background: G protein-coupled receptor (GPCRs) are large allosteric machines in that they dynamically bind extracellular and intracellular ligands or proteins to form complexes that propagate conformationally restricted cellular signals. This reciprocal allosteric system is the basis of the pluridimensional and heterogenicity of GPCR signaling. GPCRs serve as catalytic activators of heterotrimeric G-proteins (G) by exchanging GTP for the bound GDP on the G subunit. This guanine nucleotide exchange factor activity is the initial step in the G-protein cycle and determines the onset of various intracellular signaling pathways. Regulatory and accessory proteins fine-tune the intracellular signals transduced by controlling the signal amplitude and duration or acting as a scaffold for G protein-independent signaling. One of the most recent modes of signaling regulation was recognized from the discovery of the association between inactive Gi/o subunits and GoLoco (also called GPR) motif proteins an association that excludes reformation of the G·GDP/G inactive heterotrimer. The long-term objective of this research program is dedicated to the characterization of one of the smallest members of GPR motif proteins, called GPSM3 (G-protein signaling modulator type-3). Our previous work has shown that GPSM3 is prominently expressed in hematopoietic cells and have an important role in the onset of inflammatory diseases. A recent breakthrough showed that the complex Gi/o-GPSM3 directly coupled to GPCR and could serve as a novel signaling platform in lieu of the conventional G. These works open the door to study of new scaffolding proteins that organize specific signaling complexes controlling GPSM3-mediated GPCR functions. In the next five years, we will concentrate on specific objectives by answering those questions: Aim-1: What is the selectivity of GPSM3 toward GPCRs? Aim-2: What macromolecular organization controls GPSM3 selectivity and specificity? Together, these studies will constitute the basis for a better understanding of a novel GPCR regulator. We are confident this global functional approach will lead to the construction of a signaling network that will reveal a novel mechanism of signal propagation and regulation of GPCR with broad implication. The program presented will provide a great opportunity to train HQP using a combination of innovative tools and will be rewarding for participating HQP.