Plexins receive guidance cues from semaphorin ligands and transmit their signal through the plasma membrane. This family of proteins is unique amongst single-pass transmembrane receptors as their intracellular regions interact directly with several small GTPases, which regulate cytoskeletal dynamics and cell adhesion. Here, we characterize the GTPase Activating Protein (GAP) function of Plexin-B1 and find that a cooperative GAP activity towards the substrate GTPase, Rap1b, is associated with the N-terminal Juxtamembrane region of Plexin-B1. Importantly, we unveil an activation mechanism of Plexin-B1 by identifying a novel functional loop which partially blocks Rap1b entry to the plexin GAP domain. Consistent with the concept of allokairy developed for other systems, Plexin-B activity is increased by an apparent substrate mediated cooperative effect. Simulations and mutagenesis suggest the repositioned JM conformation is stabilized by the new activation switch loop when the active site is occupied, giving rise to faster enzymatic turnover and cooperative behavior.

中文翻译：

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Plexin-B通过新颖的激活开关环增强其GAP活性

丛蛋白接收来自信号量配体的指导信号，并通过质膜传递信号。该蛋白家族在单次跨膜受体中是独特的，因为它们的细胞内区域直接与调节细胞骨架动力学和细胞粘附的几个小GTP酶直接相互作用。在这里，我们表征Plexin-B1的GTPase激活蛋白（GAP）功能，并发现针对底物GTPase Rap1b的协作GAP活性与Plexin-B1的N末端近膜区域相关。重要的是，我们通过鉴定部分阻断Rap1b进入plexin GAP域的新型功能性环，揭示了Plexin-B1的激活机制。与为其他系统开发的allokairy概念一致，明显的底物介导的协同作用增加了丛蛋白-B的活性。模拟和诱变表明，当活性位点被占用时，新的激活开关环可稳定重新定位的JM构象，从而产生更快的酶转化和协同行为。