Plexins are GTPase-Activating Proteins in autoinhibited state and can be activated by induced dimerization
作者单位：State key laboratory of silkworm genome biology Southwest university Department of Pharmacology University of Texas SouthwesternMedical Center Department of Neuroscience University of Texas SouthwesternMedical Center Department of Psychiatry University of Texas SouthwesternMedical Center
会议名称：《第四届中国结构生物学学术讨论会》
会议日期：2013年
学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术]
摘 要：Plexins are cell surface receptors that bind to semaphorins and transduce signals that regulate neuronal development, immune responses, and other processes. Signaling through plexins has been proposed to rely on specific guanosine triphosphatase（GTPase）–activating protein（GAP） activity for R-Ras and M-Ras. The intracellular region of plexins is essential for signaling and contains a R-Ras/M-Ras GTPase activating protein（GAP） domain that is divided into two segments by a Rho GTPase-binding domain（RBD）. Activation of this GAP activity of plexins appears to require simultaneous binding of semaphorin to the plexin extracellular domain and of the Rho GTPases Rac1 or Rnd1 to the cytoplasmic region. However, GAP activity of plexins has eluded detection in several recent studies. Here we report the crystal structure of the plexin A3 intracellular region. The structure shows that the N- and C-terminal portions of the GAP homologous regions together form a GAP domain with an overall fold similar to other Ras GAPs. However, the plexin GAP domain adopts a closed conformation and cannot accommodate R-Ras/M-Ras in its substrate-binding site, providing a structural basis for the autoinhibited state of plexins. A comparison with the plexin B1 RBD/Rnd1 complex structure suggests that Rnd1 binding alone does not induce a conformational change in plexin, explaining the requirement of both semaphorin and a Rho GTPase for activation. The structure also identifies an N-terminal segment that is important for regulation. Both the N-terminal segment and the RBD make extensive interactions with the GAP domain, suggesting the presence of an allosteric network connecting these three domains that integrates semaphorin and Rho GTPase signals to activate the GAP. Further we found that the purified cytoplasmic region of plexin uses a noncanonical catalytic mechanism to act as a GAP for Rap, but not for R-Ras or M-Ras. The RapGAP activity of plexins was autoinhibited and could be activated by induc