# Structure and mechanism of the RalGAP tumor suppressor complex

## TL;DR

This paper reveals the structure of the RalGAP tumor suppressor complex, offering insights into how it regulates cancer-related Ras signaling.

## Contribution

The study presents the first cryo-EM structure of the RalGAP complex, elucidating its architecture and functional mechanism.

## Key findings

- RalGAP forms a 58 nm tetrameric structure composed of RalGAPα and RalGAPβ subunits.
- RalGAPβ stabilizes the catalytic domain of RalGAPα, explaining the necessity of heterodimer formation.
- Tetramer formation is essential for in vivo function but not required for in vitro activity.

## Abstract

The RalGAP (GTPase activating protein) complexes are negative regulators of the Ral GTPases and thus crucial components that counteract oncogenic Ras signaling. However, no structural information on the architecture of this tumor suppressor complex is available hampering a mechanistic understanding of its functionality. Here, we present a cryo-EM structure of RalGAP that reveals an extended 58 nm tetrameric architecture comprising two heterodimers of the RalGAPα and RalGAPβ subunits. We show that the catalytic domain of RalGAPα requires stabilization by a unique domain of RalGAPβ, providing the molecular basis for why RalGAP complexes are obligatory heterodimers. Formation of RalGAP tetramers is not required for activity in vitro, but essential for function of the complex in vivo. Structural analysis of RalGAP subunit variants reported in cancer patients suggests effects on complex formation and thus functional relevance, emphasizing the significance of the obtained structural information for medical research.

The RalGAP complex is an important tumor suppressor that counteracts oncogenic Ras signaling. Here, Rasche, Klink and colleagues present the cryo-EM structure of RalGAP and provides insight into its mechanism and molecular function.