Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin.
Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin.
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DOI：
10.7554/elife.01279
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发表时间：
2013-10-01
期刊：
影响因子：
7.7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Wang Y;Pascoe HG;Brautigam CA;He H;Zhang X
Plexins are cell surface receptors that bind semaphorins and transduce signals for regulating neuronal axon guidance and other processes. Plexin signaling depends on their cytoplasmic GTPase activating protein (GAP) domain, which specifically inactivates the Ras homolog Rap through an ill-defined non-canonical catalytic mechanism. The plexin GAP is activated by semaphorin-induced dimerization, the structural basis for which remained unknown. Here we present the crystal structures of the active dimer of zebrafish PlexinC1 cytoplasmic region in the apo state and in complex with Rap. The structures show that the dimerization induces a large-scale conformational change in plexin, which opens the GAP active site to allow Rap binding. Plexin stabilizes the switch II region of Rap in an unprecedented conformation, bringing Gln63 in Rap into the active site for catalyzing GTP hydrolysis. The structures also explain the unique Rap-specificity of plexins. Mutational analyses support that these mechanisms underlie plexin activation and signaling. DOI: http://dx.doi.org/10.7554/eLife.01279.001 A key question in neurobiology is how the brain becomes wired up. How do axons—the ‘wires’ along which neural signals flow—know in which direction to grow to reach their intended targets? A family of signalling proteins called semaphorins contribute to this process by acting as stop signals for axons that are heading in the wrong direction. The actions of semaphorins are mediated by receptors known as plexins, which are found on the membranes of axons. Plexins contain an extracellular domain that binds semaphorin, and a large domain inside the cell that can turn semaphorin binding into cellular responses. When a semaphorin protein binds to the extracellular domain of a plexin receptor, the domain inside the cell joins with the intracellular domain of a neighbouring receptor to form a dimer. This activates the intracellular domain, which turns on its ability to inactivate a molecule called Rap. The end result is that the axon stops growing and changes direction, but the molecular mechanisms through which these events occur are not well understood. Now, Wang, Pascoe et al. have worked out the structure of the dimers formed by the intracellular plexin domains, both alone and in complex with Rap. The structures reveal how the dimer drives a shape change of the intracellular domain to enable it to bind Rap, and show that Rap itself adopts a novel conformation upon binding to plexin. This conformational change in Rap catalyses the breakdown of a signalling molecule called GTP, which inactivates Rap and triggers an intracellular signalling cascade that causes the axon to collapse and change direction. Lastly, Wang, Pascoe et al. have shown that the highly specific nature of these interactions depends on particular amino-acid residues in both Rap and the plexin receptor. Further work is now required to determine whether this pattern of activation represents a general mechanism for signalling by plexin receptors, and for the inhibition of Rap. DOI: http://dx.doi.org/10.7554/eLife.01279.002
