Mechanism of the RalGAP tumor suppressor complex

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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.