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Novel Mechanisms Regulating the Heterotrimeric G Protein Complex

调节异源三聚体 G 蛋白复合物的新机制

基本信息

批准号：
8209077
负责人：
ALAN M. JONES
金额：
$ 33.56万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209077
关键词：
Abate Adaptor Signaling Protein Affect Animal Model Apical Arabidopsis Binding Biochemical Biological Assay Biological Models Boxing Caenorhabditis elegans Cell Proliferation Cell Surface Receptors Cell surface Cells Chronic Collaborations Collection Complex Coupled Coupling Data Disease Dissociation Drosophila melanogaster Drug Delivery Systems Elements Engineering Equilibrium Eukaryota Figs - dietary G Protein-Coupled Receptor Genes GTP Binding GTP-Binding Protein Regulators GTP-Binding Proteins Genes Genetic Genetic Screening Germination Glucose Goals Growth Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Heterotrimeric GTP-Binding Proteins Homeostasis Hormones Human Human Engineering Hydrolysis In Vitro Indium Integral Membrane Protein Kinetics Length Ligand Binding Ligands Luciferases Measures Mediating Meristem Methods Modeling Molecular Molecular Genetics Mutation Neurotransmitters Nucleotides Oncogenes Organism Orthologous Gene Pathway interactions Pharmacology Pharmacotherapy Photoaffinity Labels Physiological Physiological Processes Plant Roots Plants Property Proteins Publishing RGS Proteins RGS1 gene Recombinants Regulation Regulatory Element Reporter Genes Research Role Saccharomyces Seeds Signal Pathway Signal Transduction Stem cells Stimulation of Cell Proliferation Structure Testing Transmembrane Domain Uncertainty Work Yeasts base blood glucose regulation cell behavior cell growth comparative dimer driving force drug discovery gene discovery genetic regulatory protein gluconate glucose receptor histogenesis human disease in vivo innovation insight interest meetings mutant novel nucleotide receptor physical property protein complex protein structure prototype receptor research study small molecule sugar tool

项目摘要

Hormones and neurotransmitters modulate a variety of physiological processes in cell growth and behavior. Their cognate cell surface receptors, which have seven transmembrane (7TM) domains, act by coupling to G proteins, promoting the dissociation of GDP and the subsequent loading of GTP. Signaling abates when GTP is hydrolyzed and GTPase activity is accelerated by Regulators of G Signaling (RGS) proteins having GTPase accelerating protein (GAP) activity. Recently, we discovered a naturally-occurring 7TM-RGS protein in Arabidopsis (AtRGS1) that we hypothesize to be a D-glucose receptor that has a D-glucose-dependent GAP activity. It is the first example of a receptor-GAP and is the prototype for a new class of D-glucose receptors. We also showed that the Arabidopsis G¿ subunit has rapid nucleotide exchange making nucleotide hydrolysis the rate limiting step. This property is in marked contrast to the slow nucleotide exchange property of all tested G¿ subunits where GDP release is the rate limiting step of the G protein cycle. Thus, we hypothesize that regulation of the G protein cycle is at the GTP hydrolysis step and is mediated by AtRGS1. Finally, we showed that a D-glucose metabolite dramatically increases the nucleotide hydrolysis rate of the G¿ subunit. Clearly, the Arabidopsis G protein cycle contains several interesting properties, namely activation of a G¿ subunit that does not require a GEF, regulation of the cycle at the GTP hydrolysis step, and a 7TM protein that may be the ligand-regulated GAP controlling the cycling rate. Because the Arabidopsis G¿ has the basic core structure and function of human G¿, an understanding of how the Arabidopsis G¿ activation is regulated will provide insight into novel mechanisms to control human G¿ activation. The goal here is to understand how the G¿ protein is activated in the context of sugar signaling. Both hypothesis- and discovery-driven approaches will be taken to determine precisely what structure imparts regulatory control. Our initial study of the Arabidopsis G protein cycle illustrated how the G-protein cycle can be regulated by mechanisms apart by the classical GEF. Consequently, a greater degree of plasticity of the cycle is now appreciated and new entry points for regulation are revealed. Understanding the structure underlying these new mechanisms will provide a new means to regulate other G protein cycles. In humans, 7TM receptors and RGS proteins interact either directly or indirectly via adaptor proteins; these are two of several possible mechanisms providing selectivity between receptors and RGS proteins. AtRGS1 is the most extreme example of a mechanism providing receptor-RGS protein selectivity in that both GEF and GAP are two domains on one molecule. Understanding how AtRGS1 regulates the G protein cycle in a ligand dependent manner opens up new possibilities to regulate G protein cycles through drug therapies. Finally, use of Arabidopsis as a model will enable us to solve how cells respond to D-glucose within the context of a multicellular organism.

激素和神经递质调节细胞生长和行为中的各种生理过程。它们的同源细胞表面受体具有7个跨膜（7 TM）结构域，通过偶联G 蛋白质，促进GDP的解离和随后的GTP负载。当GTP 被水解，并且GT3活性被具有GT3的G信号传导调节剂（RGS）蛋白加速促进蛋白（GAP）活性。最近，我们发现了一种天然存在的7 TM-RGS蛋白，拟南芥（AtRGS 1），我们假设它是一个D-葡萄糖受体，具有D-葡萄糖依赖性GAP 活动它是第一个GAP受体的例子，也是一类新的D-葡萄糖受体的原型。我们还发现拟南芥G <$亚基具有快速的核苷酸交换，速率限制步骤。该性质与所有测试的寡核苷酸的缓慢核苷酸交换性质形成鲜明对比。 G亚基，其中GDP释放是G蛋白循环的限速步骤。因此，我们假设， G蛋白循环的调节是在GTP水解步骤，并由AtRGS 1介导。最后，我们展示了 D-葡萄糖代谢物显著增加了G亚基的核苷酸水解速率。很显然，拟南芥G蛋白循环包含几个有趣的特性，即激活一个G亚基，不需要GEF，在GTP水解步骤调节循环，并且7 TM蛋白可能是配体调节的GAP控制循环速率。因为拟南芥G <$具有基本的核心结构和人类G <$的功能，了解拟南芥G <$激活是如何调节的，将提供深入了解控制人类G ²激活的新机制。这里的目标是了解G 蛋白质在糖信号传导的背景下被激活。假设驱动和发现驱动的方法都将以准确地确定什么样的结构赋予监管控制。我们对拟南芥G 蛋白质循环的研究阐明了G蛋白循环是如何通过经典GEF以外的机制进行调节的。因此，现在认识到周期的更大程度的可塑性，都被揭露了了解这些新机制的结构将提供一种新的手段，调节其他G蛋白循环。在人类中，7 TM受体和RGS蛋白直接或间接相互作用。间接通过衔接蛋白;这是几种可能的机制提供选择性之间的两个受体和RGS蛋白。AtRGS 1是提供受体-RGS的机制的最极端的例子蛋白质选择性，因为GEF和GAP是一个分子上的两个结构域。了解AtRGS 1 以配体依赖的方式调节G蛋白循环，为调节G蛋白开辟了新的可能性通过药物治疗循环。最后，利用拟南芥作为模型将使我们能够解决细胞如何响应转化为D-葡萄糖。