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

背景资料：G蛋白偶联受体（GPCR）是大型变构机器，因为它们动态地结合细胞外和细胞内配体或蛋白质以形成传播构象受限的细胞信号的复合物。这种相互变构系统是GPCR信号传导的多维性和异质性的基础。GPCR作为异源三聚体G蛋白（G）的催化活化剂，通过G亚基上的结合GDP交换GTP。这种鸟嘌呤核苷酸交换因子活性是G蛋白循环的初始步骤，并决定各种细胞内信号传导途径的开始。调节蛋白和辅助蛋白通过控制信号幅度和持续时间或作为G蛋白非依赖性信号传导的支架来微调细胞内信号转导。最新的信号调节模式之一是通过发现失活的Gi/o亚基与GoLoco（也称为GPR）基序蛋白之间的关联来认识的，该关联排除了G·GDP/G失活异源三聚体的重组。该研究计划的长期目标是致力于GPR基序蛋白中最小成员之一的表征，称为GPSM 3（G蛋白信号转导调节剂3型）。我们以前的工作表明，GPSM 3在造血细胞中显著表达，并在炎症性疾病的发病中起重要作用。最近的一项突破表明，复合物Gi/o-GPSM 3直接偶联到GPCR，并可作为一种新的信号平台，代替传统的G.这些工作为研究新的支架蛋白打开了大门，这些支架蛋白组织控制GPSM 3介导的GPCR功能的特定信号复合物。在接下来的五年里，我们将通过回答这些问题来专注于具体的目标：目标1：GPSM 3对GPCR的选择性是什么？目的-2：什么大分子组织控制GPSM 3的选择性和特异性？总之，这些研究将构成更好地理解一种新型GPCR调节剂的基础。我们相信，这种全球功能的方法将导致一个信号网络的建设，将揭示一个新的信号传播和GPCR的调控机制，具有广泛的意义。该计划将提供一个很好的机会，培训HQP使用创新工具的组合，并将奖励参与HQP。

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.