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首页> 外文期刊>Molecular and Cellular Biology >The Ability of GAP1IP4BP To Function as a Rap1 GTPase-Activating Protein (GAP) Requires Its Ras GAP-Related Domain and an Arginine Finger Rather than an Asparagine Thumb
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The Ability of GAP1IP4BP To Function as a Rap1 GTPase-Activating Protein (GAP) Requires Its Ras GAP-Related Domain and an Arginine Finger Rather than an Asparagine Thumb

机译：GAP1IP4BP充当Rap1 GTPase激活蛋白（GAP）的能力需要其Ras GAP相关域和精氨酸手指而不是天冬酰胺拇指

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GAP1IP4BP is a member of the GAP1 family of Ras GTPase-activating proteins (GAPs) that includes GAP1m, CAPRI, and RASAL. Composed of a central Ras GAP-related domain (RasGRD), surrounded by amino-terminal C2 domains and a carboxy-terminal PH/Btk domain, these proteins, with the notable exception of GAP1m, possess an unexpected arginine finger-dependent GAP activity on the Ras-related protein Rap1 (S. Kupzig, D. Deaconescu, D. Bouyoucef, S. A. Walker, Q. Liu, C. L. Polte, O. Daumke, T. Ishizaki, P. J. Lockyer, A. Wittinghofer, and P. J. Cullen, J. Biol. Chem. 281:9891-9900, 2006). Here, we have examined the mechanism through which GAP1IP4BP can function as a Rap1 GAP. We show that deletion of domains on either side of the RasGRD, while not affecting Ras GAP activity, do dramatically perturb Rap1 GAP activity. By utilizing GAP1IP4BP/GAP1m chimeras, we establish that although the C2 and PH/Btk domains are required to stabilize the RasGRD, it is this domain which contains the catalytic machinery required for Rap1 GAP activity. Finally, a key residue in Rap1-specific GAPs is a catalytic asparagine, the so-called asparagine thumb. By generating a molecular model describing the predicted Rap1-binding site in the RasGRD of GAP1IP4BP, we show that mutagenesis of individual asparagine or glutamine residues that lie in close proximity to the predicted binding site has no detectable effect on the in vivo Rap1 GAP activity of GAP1IP4BP. In contrast, we present evidence consistent with a model in which the RasGRD of GAP1IP4BP functions to stabilize the switch II region of Rap1, allowing stabilization of the transition state during GTP hydrolysis initiated by the arginine finger.
机译：GAP1 IP4BP 是Ras GTPase激活蛋白（GAP）的GAP1家族的成员，其中包括GAP1 m ，CAPRI和RASAL。这些蛋白质由一个中央Ras GAP相关域（RasGRD）组成，周围被氨基末端C2域和一个羧基末端PH / Btk域包围，除了GAP1 m 值得注意的是，这些蛋白质Ras相关蛋白Rap1的精氨酸手指依赖性GAP活性具有意想不到的作用（S.Kupzig，D.Deaconescu，D.Bouyoucef，SA Walker，Q.Liu，CL Polte，O.Daumke，T.Izizaki，PJ Lockyer，A。 Wittinghofer和PJ Cullen，J.Biol.Chem.281：9891-9900，2006）。在这里，我们研究了GAP1 IP4BP 充当Rap1 GAP的机制。我们显示，在不影响Ras GAP活性的同时，删除RasGRD任一侧的结构域确实会显着干扰Rap1 GAP活性。通过利用GAP1 IP4BP / GAP1 m 嵌合体，我们确定尽管需要C2和PH / Btk域来稳定RasGRD，但该域包含催化机制Rap1 GAP活动所需。最后，Rap1特异性GAP中的关键残基是催化天冬酰胺，即所谓的天冬酰胺。通过生成描述GAP1 IP4BP 的RasGRD中预测的Rap1结合位点的分子模型，我们表明诱变单个预测的结合位点附近的天冬酰胺或谷氨酰胺残基没有可检测的作用GAP1 IP4BP 的体内Rap1 GAP活性研究。相反，我们提供的证据与其中GAP1 IP4BP 的RasGRD用于稳定Rap1的开关II区，允许精氨酸指启动的GTP水解过程中的过渡态稳定的模型相符。

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