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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

基本信息

批准号：
10438664
负责人：
Gregory Gordon Tall
金额：
$ 34.32万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438664
关键词：
3-Dimensional Acute Adopted Affect Affinity Animal Model Architecture Armadillo Repeat Behavioral Assay Binding Binding Proteins Biochemical CRISPR/Cas technology Caenorhabditis elegans Cell Line Cell Proliferation Cell membrane Cells Cessation of life Chronic Complex Crystallization Data Development Drosophila genus Embryo Enzymes Essential Genes Funding G-Protein-Coupled Receptors GTP Binding GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genes Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Heterotrimeric G Protein Subunit Heterotrimeric GTP-Binding Proteins Hormones In Vitro Individual Investigation Knock-out Knockout Mice Laboratories Length Link Mammals Maps Measurement Mediating Methods Mitogen-Activated Protein Kinases Molecular Chaperones Molecular Conformation Mus Neurotransmitters Normal Cell Nucleotides Oncogenes Oncogenic Oncoproteins Pathologic Pathway interactions Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiological Post-Translational Regulation Proliferating Protein Dephosphorylation Protein Subunits Protein Truncation Proteins Publishing Reaction Regulation Research Research Personnel Resources Role Serine Serine/Threonine Phosphorylation Signal Transduction Signaling Protein Site Stimulus Structural Models Structure Surface System Technology Threonine Time Tissues United States National Institutes of Health Update Work base combinatorial embryonic stem cell melanocyte mutant protein folding success

项目摘要

Summary/Abstract: Heterotrimeric G proteins are the major intracellular enzymes that receive signals from plasma membrane G protein coupled receptors (GPCRs) and transduce them to a broad array of intracellular effectors. Our lab has contributed much to the understanding of the function of a pair of G protein regulators, Ric-8A and Ric-8B. We identified Ric-8A and Ric-8B as G protein  subunit binding proteins and showed that they possess the ability to accelerate the rate at which G subunits release GDP and bind GTP. This activity is similar to GPCR action towards G protein heterotrimers. GPCRs stimulate G protein GDP/GTP exchange for the purpose of activating the G proteins to transmit signals. We have yet to find conclusive evidence that Ric-8 proteins facilitate G GDP/GTP exchange for signaling purposes. We did find that deletion of the Ric-8A or Ric-8B genes in mice caused embryonic lethality. Culture of Ric-8A or Ric-8B knockout embryonic stem cells that were attained from viable embryos prior to death demonstrated that the cells had dramatically reduced levels of G proteins. This prompted our investigation into the role that Ric-8 proteins have in regulating G protein abundance. We found that Ric-8 proteins are molecular chaperones that facilitate protein folding of newly made G subunits. When G proteins are made in cells lacking Ric-8 proteins, they are misfolded and rapidly degraded. We reconcile the in vitro GDP/GTP exchange stimulatory activity of Ric-8 with the folding function by proposing that Ric-8 proteins bind the intermediate of the in vitro exchange reaction in cells, newly-synthesized, nucleotide-free G proteins to facilitate first time GTP binding. Until now, all evidence indicated that Ric-8 proteins acted constitutively to fold G proteins. The premise of this new application is based on our recent data that show that Ric-8 activities are subject to dramatic regulation by post-translational phosphorylation. We will investigate a new link between mitogenic oncogene stimulus that leads to Ric-8 deregulation (dephosphorylation) and possible remodeling of cellular G protein levels. We have made important strides in our long-time collaborative efforts to investigate the structural basis by which Ric-8 proteins regulate G proteins. The work in this application will define the way that phosphorylation regulates Ric-8 function.

摘要/文摘:

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structures of Ric-8B in complex with Gα protein folding clients reveal isoform specificity mechanisms.

Ric-8B 与 Gα 蛋白折叠客户复合物的结构揭示了亚型特异性机制。

DOI：
10.1016/j.str.2023.02.011
发表时间：
2023
期刊：
Structure (London, England : 1993)
影响因子：
0
作者：
Papasergi-Scott,MakaíaM;Kwarcinski,FrankE;Yu,Maiya;Panova,Ouliana;Ovrutsky,AnnM;Skiniotis,Georgios;Tall,GregoryG
通讯作者：
Tall,GregoryG

Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQ(Q209L)-driven melanoma.

DOI：
10.1038/oncsis.2016.45
发表时间：
2016-06-27
期刊：
Oncogenesis
影响因子：
6.2
作者：
Patel BR;Tall GG
通讯作者：
Tall GG

Ric-8 regulation of heterotrimeric G proteins.

Ric-8 异源三聚体 G 蛋白的调节。

DOI：
10.3109/10799893.2013.763828
发表时间：
2013
期刊：
Journal of receptor and signal transduction research
影响因子：
0
作者：
Tall,GregoryG
通讯作者：
Tall,GregoryG

Ric-8 proteins are molecular chaperones that direct nascent G protein α subunit membrane association.

RIC-8蛋白是直接新生G蛋白α亚基膜关联的分子伴侣。

DOI：
10.1126/scisignal.2002223
发表时间：
2011-11-22
期刊：
Science signaling
影响因子：
7.3
作者：
Gabay M;Pinter ME;Wright FA;Chan P;Murphy AJ;Valenzuela DM;Yancopoulos GD;Tall GG
通讯作者：
Tall GG

The tethered peptide activation mechanism of adhesion GPCRs.