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首页> 外文期刊>Biochemistry >Activation of the Regulator of G Protein Signaling 14−Gαi1-GDP Signaling Complex Is Regulated by Resistance to Inhibitors of Cholinesterase-8A
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Activation of the Regulator of G Protein Signaling 14−Gαi1-GDP Signaling Complex Is Regulated by Resistance to Inhibitors of Cholinesterase-8A

机译：G蛋白信号传导14-Gαi1-GDP信号传导复合物调节因子的激活受胆碱酯酶8A抑制剂的抗性调节。

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RGS14 is a brain scaffolding protein that integrates G protein and MAP kinase signalingnpathways. Like otherRGS proteins,RGS14 is aGTPase activating protein (GAP) that terminatesGRi/o signaling.nUnlike other RGS proteins, RGS14 also contains a G protein regulatory (also known as GoLoco) domain thatnbinds GRi1/3-GDP in cells and in vitro. Here we report that Ric-8A, a nonreceptor guanine nucleotide exchangenfactor (GEF), functionally interacts with the RGS14-GRi1-GDP signaling complex to regulate its activation state.nRGS14 and Ric-8A are recruited from the cytosol to the plasma membrane in the presence of coexpressed GRi1 inncells, suggesting formation of a functional protein complex with GRi1. Consistent with this idea, Ric-8A stimulatesndissociation of the RGS14-GRi1-GDP complex in cells and in vitro using purified proteins. Purified Ric-8Anstimulates dissociation of the RGS14-GRi1-GDP complex to form a stable Ric-8A-GRi complex in the absencenof GTP. In the presence of an activating nucleotide, Ric-8A interacts with the RGS14-GRi1-GDP complex tonstimulate both the steady-state GTPase activity of GRi1 and binding of GTP to GRi1.However,sufficientlyhighnconcentrations of RGS14 competitively reverse these stimulatory effects of Ric-8A onGRi1 nucleotide binding andnGTPase activity. This observation correlates with findings that show RGS14 and Ric-8A share an overlappingnbinding region within the last 11 amino acids of GRi1. As further evidence that these proteins are functionallynlinked, native RGS14 and Ric-8A coexist within the same hippocampal neurons. These findings demonstrate thatnRGS14 is a newly appreciated integrator of unconventional Ric-8A and GRi1 signaling
机译：RGS14是整合G蛋白和MAP激酶信号通路的大脑支架蛋白。与其他RGS蛋白一样，RGS14是一种GTPase激活蛋白（GAP），可终止GRi / o信号传导。与其他RGS蛋白不同，RGS14还包含一个G蛋白调节域（也称为GoLoco），该域将GRi1 / 3-GDP结合在细胞和体外。在这里我们报告Ric-8A，一种非受体鸟嘌呤核苷酸交换因子（GEF），在功能上与RGS14-GRi1-GDP信号复合物相互作用以调节其激活状态.nRGS14和Ric-8A从细胞质中募集到细胞膜中。共表达GRi1 inncells的存在，表明与GRi1形成功能蛋白复合物。与此想法一致，Ric-8A使用纯化的蛋白质刺激细胞和体外的RGS14-GRi1-GDP复合物解离。在没有GTP的情况下，纯化的Ric-8刺激RGS14-GRi1-GDP复合物解离，形成稳定的Ric-8A-GRi复合物。在存在激活核苷酸的情况下，Ric-8A与RGS14-GRi1-GDP复合物相互作用，同时刺激GRi1的稳态GTPase活性和GTP与GRi1的结合。然而，足够高的RGS14浓度竞争性地逆转了Ric-A的这些刺激作用。图8A关于GRi1核苷酸结合和nGTP酶活性。该观察结果与显示RGS14和Ric-8A在GRi1的最后11个氨基酸内共有一个重叠的结合区域的发现相关。作为这些蛋白质功能性连接的进一步证据，天然RGS14和Ric-8A共存于同一海马神经元中。这些发现表明，nRGS14是非常规Ric-8A和GRi1信号的新整合者

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