The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction
The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction
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DOI：
10.1038/embor.2008.20
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发表时间：
2008-04-01
期刊：
影响因子：
7.7
通讯作者：
Scheffzek, Klaus
中科院分区：
文献类型：
--
作者：
Pena, Vladimir;Hothorn, Michael;Scheffzek, Klaus
脑特异性突触鸟苷三磷酸酶激活蛋白（SynGAP）在突触可塑性中起重要作用。它对小鸟嘌呤核苷酸结合蛋白Rap和Ras具有双重特异性。在这里，我们表明SynGAP的RapGAP活性需要其C2结构域。与不显示任何可检测的RapGAP活性的分离的GAP结构域相反，包含C2和GAP结构域（C2-GAP）的片段刺激Rap的内在GT3反应约1 × 10（4）。C2 - GAP晶体结构，通过建模和生化分析补充，有利于C2结构域向Rap的开关II区域的协调运动，以帮助GT3刺激。我们的数据支持一个催化机制，类似于典型的RasGAP和不同的典型RapGAP。据我们所知，SynGAP提出了第一个使用第二个结构域进行催化活性的GAP的例子，从而指出了C2结构域的新功能。
The brain-specific synaptic guanosine triphosphatase ( GTPase)activating protein ( SynGAP) is important in synaptic plasticity. It shows dual specificity for the small guanine nucleotide-binding proteins Rap and Ras. Here, we show that RapGAP activity of SynGAP requires its C2 domain. In contrast to the isolated GAP domain, which does not show any detectable RapGAP activity, a fragment comprising the C2 and GAP domains (C2-GAP) stimulates the intrinsic GTPase reaction of Rap by approximately 1 x 10(4). The C2 - GAP crystal structure, complemented by modelling and biochemical analyses, favours a concerted movement of the C2 domain towards the switch II region of Rap to assist in GTPase stimulation. Our data support a catalytic mechanism similar to that of canonical RasGAPs and distinct from the canonical RapGAPs. SynGAP presents the first example, to our knowledge, of a GAP that uses a second domain for catalytic activity, thus pointing to a new function of C2 domains.