Wittinghofer A, Scheffzek K, Ahmadian M R
Max-Planck-Institut für molekulare Physiologie, Dortmund, Germany.
FEBS Lett. 1997 Jun 23;410(1):63-7. doi: 10.1016/s0014-5793(97)00321-9.
Ras plays a major role as a molecular switch in many signal transduction pathways which lead to cell growth and differentiation. The GTPase reaction of Ras is of central importance in the function of the switch since it terminates Ras-effector interactions. GTPase-activating proteins (GAPs) accelerate the very slow intrinsic hydrolysis reaction of the GTP-bound Ras by several orders of magnitude and thereby act as presumably negative regulators of Ras action. The GTP hydrolysis of oncogenic mutants of Ras remains unaltered. In this review we discuss recent biochemical and structural findings relating to the mechanism of GAP action, which strengthen the hypothesis that GAP accelerates the actual cleavage step by stabilizing the transition state of the phosphoryl transfer reaction.
Ras在许多导致细胞生长和分化的信号转导途径中作为分子开关发挥着主要作用。Ras的GTP酶反应在开关功能中至关重要，因为它终止了Ras与效应器的相互作用。GTP酶激活蛋白（GAPs）将与GTP结合的Ras非常缓慢的内在水解反应加速了几个数量级，从而可能作为Ras作用的负调节因子。Ras致癌突变体的GTP水解保持不变。在本综述中，我们讨论了与GAP作用机制相关的最新生化和结构研究结果，这些结果强化了GAP通过稳定磷酰转移反应的过渡态来加速实际裂解步骤的假说。
