Scheffzek K, Lautwein A, Kabsch W, Ahmadian M R, Wittinghofer A
Max-Planck-Institut für molekulare Physiologie, Dortmund, Germany.
Nature. 1996 Dec 12;384(6609):591-6. doi: 10.1038/384591a0.
Ras-related GTP-binding proteins function as molecular switches which cycle between GTP-bound 'on'- and GDP-bound 'off'-states. GTP hydrolysis is the common timing mechanism that mediates the return from the 'on' to the 'off'-state. It is usually slow but can be accelerated by orders of magnitude upon interaction with GTPase-activating proteins (GAPs). In the case of Ras, a major regulator of cellular growth, point mutations are found in approximately 30% of human tumours which render the protein unable to hydrolyse GTP, even in the presence of Ras-GAPs. The first structure determination of a GTPase-activating protein reveals the catalytically active fragment of the Ras-specific p120GAP (ref. 2), GAP-334, as an elongated, exclusively helical protein which appears to represent a novel protein fold. The molecule consists of two domains, one of which contains all the residues conserved among different GAPs for Ras. From the location of conserved residues around a shallow groove in the central domain we can identify the site of interaction with Ras x GTP. This leads to a model for the interaction between Ras and GAP that satisfies numerous biochemical and genetic data on this important regulatory process.
与Ras相关的GTP结合蛋白起着分子开关的作用，在结合GTP的“开启”状态和结合GDP的“关闭”状态之间循环。GTP水解是介导从“开启”状态回到“关闭”状态的常见定时机制。它通常很缓慢，但与GTP酶激活蛋白（GAP）相互作用时可加快几个数量级。就细胞生长的主要调节因子Ras而言，在大约30%的人类肿瘤中发现了点突变，这些突变使该蛋白即使在存在Ras-GAP的情况下也无法水解GTP。GTP酶激活蛋白的首次结构测定揭示了Ras特异性p120GAP（参考文献2）的催化活性片段GAP-334是一种细长的、仅由螺旋构成的蛋白，它似乎代表了一种新的蛋白质折叠形式。该分子由两个结构域组成，其中一个结构域包含不同的Ras GAP中所有保守的残基。从中央结构域中一个浅沟周围保守残基的位置，我们可以确定与Ras x GTP相互作用的位点。这就产生了一个Ras与GAP之间相互作用的模型，该模型符合关于这一重要调节过程的大量生化和遗传数据。
