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Decoding the phosphorylation bar code in Arabidopsis G Biased Signaling

解码拟南芥 G 偏向信号传导中的磷酸化条形码

基本信息

批准号：
10611322
负责人：
ALAN M. JONES
金额：
$ 37.86万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611322
关键词：
Abate Acceleration Agonist Amino Acids Animals Arabidopsis Bar Codes Cell Surface Receptors Cell membrane Cells Code Complement Complex Core Protein Coupled Coupling Discrimination Dissociation Elements Endocytosis Eukaryota Evolution Flagellin Four-dimensional G-Protein-Coupled Receptors GTP-Binding Protein Regulators GTP-Binding Proteins Gene Expression Genetic Genetic Models Glucose Grant Guanine Nucleotides Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Heterotrimeric GTP-Binding Proteins Hormones Human Human Engineering Hydrolysis Label Ligands Location MAP Kinase Gene Membrane Molecular Motion Neighborhoods Neurotransmitters Nucleotides Organism Outcome Pathway interactions Pattern Pharmacotherapy Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiological Processes Plants Property Proteins RGS Proteins Reading Regulation Resolution Rest Role Signal Induction Signal Pathway Signal Transduction Signaling Protein Site Structure Subcellular Spaces System Testing Time Transmembrane Domain Variant Work Writing Yeasts cell behavior cell growth derepression encryption experimental study gain of function in vivo loss of function mutation new therapeutic target novel pathogen pathogenic bacteria pharmacologic protein activation protein complex protein protein interaction prototype rate of change receptor recruit response segregation sugar nucleotide tool trafficking

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 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 proteins having GTPase accelerating protein (GAP) activity. Recently, we discovered a naturally-occurring 7TM-RGS protein in Arabidopsis (AtRGS1) that is a glucose or nucleotide-sugar receptor. It is the prototype of a receptor-GAP. We also showed that the Arabidopsis Gα subunit (AtGPA1) 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 Gα subunits where GDP release is the rate limiting step of the G protein cycle. In contrast to animals, regulation of the G protein cycle is at the GTP hydrolysis step and is modulated by AtRGS1. This level of modulation is controlled by reversible phosphorylation of AtRGS1 and AtGPA1 at a mostly undeciphered set of phosphorylated amino acids designated here as the collective phospho-bar code. We do know that one phosphorylation pattern on AtRGS1 is necessary and sufficient to initiate AtRGS1 endocytosis and another on AtGPA1 changes the rate of AtRGS1-dependent G cycling. There are different clusters of complexes of the AtRGS1/G protein/kinase/phosphatase on the plasma membrane and these different clusters are activated by different agonists. Furthermore, we hypothesize that this initial clustering, the assortment of proteins in the cluster, and the subsequent trafficking of the cluster components after activation is encrypted by the phospho-bar code. Using the power of a genetic system will enable us to determine the physiological role of the bar code in a multicellular context. Both hypothesis- and discovery-driven approaches will be taken to determine precisely what structure imparts regulatory control. Our studies of the Arabidopsis G protein cycle have to date illustrated how the G-protein cycle can be regulated by mechanisms distinct from 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. Understanding how AtRGS1 modulates the G protein cycle in a ligand-dependent manner opens up new possibilities to regulate G protein cycles through drug therapies. The core elements of heterotrimeric G protein coupled signaling are conserved in eukaryotes but the mechanism to regulate the active state of the G protein is not. This variation, genetically encoded in organisms divergent by as much as 1.6 billion years of evolution, represents the full range of plasticity of the G protein signaling system. Understanding this plasticity will reveal novel ways to regulate G signaling in humans.

激素和神经递质调节细胞生长中的多种生理过程，行为它们的同源细胞表面受体有7个跨膜结构域， G蛋白，促进GDP的解离和随后的GTP负载。信号减弱当GTP被水解并且GTP酶活性被G信号蛋白的调节剂加速时，谷胱甘肽加速蛋白（GAP）活性。最近，我们发现了一种天然存在的7 TM-RGS 拟南芥中的一种蛋白质（AtRGS 1），是葡萄糖或核苷酸-糖受体。它是一个受体间隙。我们还发现拟南芥Gα亚基（AtGPA 1）具有快速的核苷酸交换，使核苷酸水解成为限速步骤。这种特性与缓慢的所有测试的Gα亚基的核苷酸交换性质，其中GDP释放是Gα亚基的限速步骤。 G蛋白循环。与动物相反，G蛋白循环的调节是在GTP水解步骤，由AtRGS 1调节。这种调节水平由AtRGS 1的可逆磷酸化控制和AtGPA 1在一组大多未破译的磷酸化氨基酸上，在这里被指定为集体磷光条形码我们确实知道AtRGS 1上的一种磷酸化模式是必要和充分的，启动AtRGS 1的内吞作用，另一个作用于AtGPA 1，改变AtRGS 1依赖的G循环速率。在血浆上存在不同的AtRGS 1/G蛋白/激酶/磷酸酶复合物簇膜和这些不同的簇被不同的激动剂激活。此外，我们假设这种最初的聚类，聚类中蛋白质的分类，以及随后的蛋白质运输，激活后的群集组件由磷光条形码加密。利用基因的力量该系统将使我们能够确定条形码在多细胞环境中的生理作用。两假设和发现驱动的方法将被用来精确地确定结构赋予了什么监管控制。我们对拟南芥G蛋白周期的研究迄今为止已经阐明了G蛋白是如何可通过与传统全球环境基金不同的机制来调节循环。因此，更大程度的现在认识到了周期的可塑性，并揭示了新的调节切入点。理解这些新机制结构将为调节其他G蛋白提供新的手段自行车.了解AtRGS 1如何以配体依赖性方式调节G蛋白周期通过药物疗法调节G蛋白循环的新可能性。的核心要素异源三聚体G蛋白偶联信号在真核生物中是保守的，但调节G蛋白偶联信号的机制在真核生物中是保守的。 G蛋白的活性状态则不然。这种变异，在生物体中的基因编码，作为16亿年的进化，代表了G蛋白信号系统的全部可塑性。了解这种可塑性将揭示调节人类G信号的新方法。