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Structure and mechanism of the RalGAP tumor suppressor complex

Author

Listed:
  • René Rasche

    (University of Münster)

  • Björn Udo Klink

    (University of Münster
    University of Münster)

  • Lisa Helene Apken

    (University of Münster)

  • Esther Michalke

    (University of Münster)

  • Minghao Chen

    (University of Münster
    University of Münster)

  • Andrea Oeckinghaus

    (University of Münster
    University Alliance Ruhr & University Hospital Essen)

  • Christos Gatsogiannis

    (University of Münster
    University of Münster)

  • Daniel Kümmel

    (University of Münster)

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.

Suggested Citation

  • René Rasche & Björn Udo Klink & Lisa Helene Apken & Esther Michalke & Minghao Chen & Andrea Oeckinghaus & Christos Gatsogiannis & Daniel Kümmel, 2025. "Structure and mechanism of the RalGAP tumor suppressor complex," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61743-9
    DOI: 10.1038/s41467-025-61743-9
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