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首页> 外文期刊>Journal of Molecular Biology >Noncanonical Myo9b-RhoGAP Accelerates RhoA GTP Hydrolysis by a Dual-Arginine-Finger Mechanism
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Noncanonical Myo9b-RhoGAP Accelerates RhoA GTP Hydrolysis by a Dual-Arginine-Finger Mechanism

机译：非经典的Myo9b-RhoGAP通过双精氨酸-指机制加速RhoA GTP水解。

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摘要

The GTP hydrolysis activities of Rho GTPases are stimulated by GTPase-activating proteins (GAPs), which contain a RhoGAP domain equipped with a characteristic arginine finger and an auxiliary asparagine for catalysis. However, the auxiliary asparagine is missing in the RhoGAP domain of Myo9b (Myo9b-RhoGAP), a unique motorized RhoGAP that specifically targets RhoA for controlling cell motility. Here, we determined the structure of Myo9b-RhoGAP in complex with GDP-bound RhoA and magnesium fluoride. Unexpectedly, Myo9b-RhoGAP contains two arginine fingers at its catalytic site. The first arginine finger resembles the one within the canonical RhoGAP domains and inserts into the nucleotide-binding pocket of RhoA, whereas the second arginine finger anchors the Switch I loop of RhoA and interacts with the nucleotide, stabilizing the transition state of GTP hydrolysis and compensating for the lack of the asparagine. Mutating either of the two arginine fingers impaired the catalytic activity of Myo9b-RhoGAP and affected the Myo9b-mediated cell migration. Our data indicate that Myo9b-RhoGAP accelerates RhoA GTP hydrolysis by a previously unknown dual-arginine-finger mechanism, which may be shared by other noncanonical RhoGAP domains lacking the auxiliary asparagine. (C) 2016 Elsevier Ltd. All rights reserved.
机译：Rho GTPases的GTP水解活性受到GTPase激活蛋白（GAP）的刺激，该蛋白包含一个RhoGAP域，该域配备有特征性的精氨酸指和辅助天冬酰胺以进行催化。但是，辅助天冬酰胺在Myo9b（Myo9b-RhoGAP）的RhoGAP域中缺失，Mho9b是一种独特的机动RhoGAP，其专门针对RhoA来控制细胞运动。在这里，我们确定了Myo9b-RhoGAP与GDP结合的RhoA和氟化镁复合物的结构。出乎意料的是，Myo9b-RhoGAP在其催化位点包含两个精氨酸指。第一个精氨酸手指类似于RhoGAP规范域中的一个，并插入RhoA的核苷酸结合口袋，而第二个精氨酸手指锚定RhoA的Switch I环并与核苷酸相互作用，从而稳定了GTP水解的过渡态并补偿了因为缺乏天冬酰胺。两个精氨酸手指中的任何一个突变都会削弱Myo9b-RhoGAP的催化活性，并影响Myo9b介导的细胞迁移。我们的数据表明，Myo9b-RhoGAP通过先前未知的双精氨酸-指机制加速RhoA GTP水解，这可能与缺乏辅助天冬酰胺的其他非规范RhoGAP域共享。 （C）2016 Elsevier Ltd.保留所有权利。

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