Investigation of Adhesion GPCR and Ric-8 protein control of heterotrimeric G proteins
异三聚体 G 蛋白粘附 GPCR 和 Ric-8 蛋白控制的研究
基本信息
- 批准号:10622696
- 负责人:
- 金额:$ 19.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:ADGR1 geneAdhesionsAgonistBiochemicalBiologicalBloodBlood PlateletsCell AdhesionCell membraneCellsCellular biologyComplexDiseaseDissociationDrosophila genusElementsEventExtracellular MatrixFamilyFamily memberG-Protein-Coupled ReceptorsGTP-Binding Protein alpha SubunitsGTP-Binding ProteinsGeneticGoalsGuanine NucleotidesHeterotrimeric GTP-Binding ProteinsInvestigationLigandsMolecular ChaperonesProtein BiochemistryProteinsSeriesSignal TransductionSpecificityStructureSubstrate SpecificitySumSystemTechniquesTransmembrane DomainWorkcell typeexperimental studyextracellularin vivomembermouse modelprotein complexreceptorresponse
项目摘要
Project Summary: This MIRA proposal will combine work from our longstanding projects on the structure and
function of adhesion G protein coupled receptors (or Family B2 GPCRs) and the molecular chaperones for G
protein alpha subunits, Ric-8 proteins. Adhesion GPCRs are a large, 33-member family of receptors that
transduce signals from cell to cell or cell to extracellular matrix adhesion events across the cell membrane to
awaiting G proteins in order to elicit responses within the cell. Our work has advanced a mechanism for adhesion
GPCR activation in which the extracellular adhesion domains become anchored to protein ligands and the cell
that contains the GPCR or seven transmembrane domain (7TM) moves, by any number of means, in relation to
this fixed anchor to dissociate the two halves of the adhesion GPCR. This dissociation event reveals a previously
hidden tethered agonist of the GPCR/7TM domain that self-activates the receptor. This mode of activation
seems common to most members of the adhesion GPCR family, but alternative modes of adhesion GPCR
activation have also come to the fore of the field. Our goal in this proposal is to expand upon our mechanistic
and structural work to decipher varied adhesion GPCR activation modes using biochemical, cell biological, and
in vivo approaches, including work with two mouse models newly created for this proposal. We will focus on
adhesion GPCRs that are present in cells that circulate in the blood, for example ADGRG1/GPR56 on platelets,
as well as additional ADGRG subfamily members present on other circulating cell types. Circulating cells offer
an advantage for interrogating adhesion GPCR action because the shear force component that dissociates the
two fragments of the receptors, for the purpose of tethered-agonist-activation, is readily tractable. The sum of
our work will be to distinguish tethered agonist -dependent and -independent modes of adhesion GPCR
activation, which we argue is perhaps the most important contemporary question in the adhesion GPCR field.
In parallel, we have assigned the function of Ric-8A and Ric-8B proteins as molecular chaperones that are
required to collectively fold all G protein alpha subunits. This is a mature project for our lab, yet we have made
recent breakthroughs in solving the structures of Ric-8/G protein guanine nucleotide-free complexes. We
present preliminary evidence of a new Ric-8/G protein complex structure that will enable us to finally tackle a
major outstanding question; What are the structural elements of mammalian Ric-8A and Ric-8B that define their
specificities for different G protein subtypes? Combined with analysis of the single copy of an ancestral Ric-8
(Drosophila Ric-8) that seemingly crosses the lines and appears to fold all G protein subtypes, our work will
provide new understanding of the substrate specificity rules, thereby providing a rationale for potentially targeting
the Ric-8 chaperone system in contexts of G protein-driven disease.
项目摘要:MIRA的这一建议将联合收割机的工作,从我们的长期项目的结构和
粘附G蛋白偶联受体(或B2家族GPCR)和G蛋白分子伴侣的功能
蛋白质α亚基,Ric-8蛋白。粘附GPCR是一个由33个成员组成的受体大家族,
细胞与细胞或细胞与细胞外基质之间的粘附信号通过细胞膜传递,
等待G蛋白来引发细胞内的反应。我们的工作提出了一种粘附机制
GPCR激活,其中细胞外粘附结构域锚定到蛋白质配体和细胞
包含GPCR或七个跨膜结构域(7 TM)的分子通过任何数量的手段移动,
该固定的锚使粘附GPCR的两半分离。这个分离事件揭示了一个先前的
自激活受体的GPCR/7 TM结构域的隐藏的束缚激动剂。这种激活模式
似乎常见于粘附GPCR家族的大多数成员,但粘附GPCR的替代模式
激活也来到了该领域的前沿。我们在这个提案中的目标是扩大我们的机械
和结构工作,以破译不同的粘附GPCR激活模式,使用生物化学,细胞生物学,
在体内的方法,包括工作与两个新创建的小鼠模型,这一建议。我们将专注于
存在于血液中循环的细胞中的粘附GPCR,例如血小板上的ADGRG 1/GPR 56,
以及存在于其它循环细胞类型上的其它ADGRG亚家族成员。循环细胞提供
询问粘附GPCR作用的优点是,
受体的两个片段用于束缚激动剂激活的目的是容易处理的。的总和
我们的工作将是区分依赖激动剂和非依赖激动剂的GPCR粘附模式
活化,我们认为这可能是最重要的当代问题,在粘附GPCR领域。
同时,我们已经指定Ric-8A和Ric-8B蛋白作为分子伴侣的功能,
所有G蛋白α亚基的折叠所需的。这是我们实验室的一个成熟项目,但我们已经做出了
最近在解决Ric-8/G蛋白鸟嘌呤无核苷酸复合物的结构方面取得了突破。我们
提出了一种新的Ric-8/G蛋白复合物结构的初步证据,这将使我们能够最终解决一个问题。
一个主要的悬而未决的问题;哺乳动物Ric-8A和Ric-8B的结构元件是什么,
不同G蛋白亚型的特异性?结合对祖先Ric-8单拷贝的分析,
(果蝇Ric-8)似乎跨越了界限,似乎折叠了所有的G蛋白亚型,我们的工作将
提供了对底物特异性规则的新理解,从而为潜在靶向提供了理论基础
Ric-8分子伴侣系统在G蛋白驱动疾病中的作用
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gregory Gordon Tall其他文献
Gregory Gordon Tall的其他文献
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{{ truncateString('Gregory Gordon Tall', 18)}}的其他基金
Development of Chemical Probes to Investigate Adhesion GPCR Tethered Agonism
开发用于研究粘附 GPCR 系链激动作用的化学探针
- 批准号:
9917826 - 财政年份:2018
- 资助金额:
$ 19.73万 - 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
- 批准号:
8534176 - 财政年份:2009
- 资助金额:
$ 19.73万 - 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
- 批准号:
9336939 - 财政年份:2009
- 资助金额:
$ 19.73万 - 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
- 批准号:
8136505 - 财政年份:2009
- 资助金额:
$ 19.73万 - 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
- 批准号:
8757091 - 财政年份:2009
- 资助金额:
$ 19.73万 - 项目类别:
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