Journal Article

PUBDB-2025-04141

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The GTPase κB-Ras is an essential subunit of the RalGAP tumor suppressor complex

Rasche, R. ; Apken, L. H. ; Titze, S. ; Michalke, E. ; Singh, R. K. ; Oeckinghaus, A. ; Kuemmel, D. (Corresponding author)Extern*EMBL*

2025
American Soc. for Biochemistry and Molecular Biology Bethesda, MD

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Please use a persistent id in citations: doi:10.1016/j.jbc.2025.110460  doi:10.3204/PUBDB-2025-04141

Abstract: κB-Ras1 and κB-Ras2 are small GTPases with noncanonical features that act as tumor suppressors downstream of Ras. Via interaction with the RalGAP (GTPase-activating protein) complex, they limit activity of Ral GTPases and restrict anchorage-independent proliferation. We here present the crystal structure of κB-Ras1 in complex with the N-terminal domain of RGα2. The structure suggests a mechanism of intrinsic GTP hydrolysis of κB-Ras1 that relies on a scaffolding function of the GTPase rather than on catalytic residues, which we confirm by mutational analysis. The interaction with RGα2 is nucleotide independent and does not involve κB-Ras1 switch regions, which establishes κB-Ras proteins as a constitutive third subunit of RalGAP complexes. Functional studies demonstrate that κB-Ras proteins are not required for RalGAP catalytic activity in vitro but for functionality in vivo. We propose that κB-Ras may thus act as a regulator of RalGAP localization and thereby control the Ras–Ral signaling pathway.

Note: ISSN 0021-9258 not unique: **2 hits**. This work was supported bygrants from Deutsche Forschungsgemeinschaft (DFG, GermanResearch Foundation; grant no.: KU2531/6-1; to D. K. and grantno.: OE531/4-1; to A. O.).

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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