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

背景：G蛋白偶联受体（gpcr）是一种大型变构机器，它们动态结合细胞外和细胞内配体或蛋白质形成复合物，传播构象受限的细胞信号。这种互变构系统是GPCR信号多维性和异质性的基础。gpcr作为异三聚体g -蛋白（Gαβγ）的催化活化剂，将GTP交换为Gα亚基上结合的GDP。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，并决定了各种细胞内信号通路的开始。调节蛋白和辅助蛋白通过控制信号的振幅和持续时间或作为G蛋白不依赖的信号传导的支架来微调细胞内信号转导。一种最新的信号调节模式是发现无活性Gαi/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Gα·GDP/Gβγ无活性异源三聚体的重组。******该研究计划的长期目标是致力于表征GPR基序蛋白的最小成员之一，称为GPSM3 （g蛋白信号调节因子类型-3）。我们之前的工作表明GPSM3在造血细胞中显著表达，在炎症性疾病的发病中起重要作用。最近的一项突破表明，配合物Gαi/o-GPSM3直接偶联到GPCR上，可以代替传统的Gαβγ作为一种新的信号传导平台。这些工作为研究组织控制gpsm3介导的GPCR功能的特定信号复合物的新支架蛋白打开了大门。******未来5年，我们将专注于具体目标，通过回答这些问题：***目标1:GPSM3对gpcr的选择性是什么？***目的2:GPSM3的选择性和特异性是由什么大分子组织控制的？******总之，这些研究将为更好地理解一种新的GPCR调节因子奠定基础。我们相信这种全球功能方法将导致信号网络的构建，这将揭示GPCR信号传播和调控的新机制，具有广泛的意义。该项目将为HQP提供一个使用创新工具组合培训HQP的绝佳机会，并将奖励参与HQP的人员。

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 (Gαβγ) by exchanging GTP for the bound GDP on the Gα 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 Gαi/o subunits and GoLoco (also called GPR) motif proteins – an association that excludes reformation of the Gα·GDP/Gβγ 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 Gαi/o-GPSM3 directly coupled to GPCR and could serve as a novel signaling platform in lieu of the conventional Gαβγ. 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.