The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins
The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins
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DOI：
10.1126/scisignal.2004993
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发表时间：
2014-04-15
影响因子：
7.3
通讯作者：
Bustelo, Xose R.
中科院分区：
文献类型：
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作者：
Barreira, Maria;Fabbiano, Salvatore;Bustelo, Xose R.
Vav蛋白是依赖磷酸化的鸟嘌呤核苷酸交换因子(GEF)，催化鸟苷三磷酸酶(GTP酶)Rho家族成员的激活。目前的调控模型认为，这些GEF的非磷酸化、催化失活状态是通过氨基末端结构域和中心催化核心之间的分子内相互作用来维持的，这些相互作用阻止了Vav蛋白与GTP酶的结合。我们表明，这种自抑制在力学上更加复杂，还涉及Vav的羧基末端Src同源3(SH3)区域与其催化和Pleckstrin同源(PH)结构域的二价结合。这种相互作用是通过不依赖于脯氨酸的区域机制发生的。从这种双重锁定状态完全释放需要多个磷酸化酪氨酸残基的协同减弱效应，从而提供一个优化的系统来产生依赖于上游信号输入的Vav环境基金活性梯度。这一机制在哺乳动物和果蝇的黑腹果蝇Vav蛋白中是相同的，这表明它可能是该蛋白家族的共同调节特征。
Vav proteins are phosphorylation-dependent guanine nucleotide exchange factors (GEFs) that catalyze the activation of members of the Rho family of guanosine triphosphatases (GTPases). The current regulatory model holds that the nonphosphorylated, catalytically inactive state of these GEFs is maintained by intramolecular interactions among the amino-terminal domains and the central catalytic core, which block the binding of Vav proteins to GTPases. We showed that this autoinhibition is mechanistically more complex, also involving the bivalent association of the carboxyl-terminal Src homology 3 (SH3) region of Vav with its catalytic and pleckstrin homology (PH) domains. Such interactions occurred through prolinerich region-independent mechanisms. Full release from this double-locked state required synergistic weakening effects from multiple phosphorylated tyrosine residues, thus providing an optimized system to generate gradients of Vav GEF activity depending on upstream signaling inputs. This mechanism is shared by mammalian and Drosophila melanogaster Vav proteins, suggesting that it may be a common regulatory feature for this protein family.