Mechanism of the RalGAP tumor suppressor complex

Ral家族的小gtpase在各种细胞内运输和信号通路的协调中起着至关重要的作用。Rals参与控制增殖和存活，调节胞吐、内吞和自噬。由于Rals与疾病的发展有关，主要是癌症，但也与代谢综合征有关，因此Rals受到了极大的关注，并成为药物开发的目标。然而，支撑Ral GTPases功能的许多分子机制仍然是难以捉摸的。这也适用于RalGAP （Ral GTPase激活蛋白）复合物，它作为Ral GTPase的关键负调节因子，因此被描述为肿瘤抑制蛋白。RalGAP功能背后的许多分子方面，如催化机制、激活和定位，以及这些大型复合物的大部分对这些过程的贡献尚不清楚。因此，我们提出了RalGAP复合物的结构和机制表征，以获得其在调节RalGAP GTPase中的作用及其对疾病发展的贡献的新见解。

The small GTPases of the Ral family represent a crucial hub in the coordination of a variety of intracellular trafficking and signaling pathways. Rals are involved in the control of proliferation and survival, regulated exocytosis, endocytosis and autophagy. Because they have been implicated in the development of disease, primarily cancer, but also metabolic syndrome, Rals have received significant attention and are targeted for drug development. Much of the molecular mechanisms that underlie the function of Ral GTPases, however, remain elusive. This also applies to the RalGAP (Ral GTPase activating protein) complexes that act as key negative regulators of Ral GTPases and are therefore described as tumor suppressor proteins. Many of the molecular aspects underlying RalGAP function, like catalytic mechanism, activation and localization, and the contributions of most parts of these large complexes to these processes are not understood. We thus propose the structural und mechanistic characterization of RalGAP complex to gain novel insight into their role in the regulation of Ral GTPase and their contribution to the development of disease.