Structures of RGL1 RAS-Association Domain in Complex with KRAS and the Oncogenic G12V Mutant

• Published in: Journal of molecular biology 2022-05, Vol.434 (9), p.167527-167527, Article 167527
• Main Authors: Eves, Ben J., Gebregiworgis, Teklab, Gasmi-Seabrook, Geneviève M.C., Kuntz, Douglas A., Privé, Gilbert G., Marshall, Christopher B., Ikura, Mitsuhiko
• Format: Article
• Language: English
• Subjects: cancer biology; GTPase KRAS (KRAS); Guanine Nucleotide Exchange Factors - chemistry; Humans; Mutation; nuclear magnetic resonance (NMR); Protein Domains; Proto-Oncogene Proteins p21(ras) - chemistry; Proto-Oncogene Proteins p21(ras) - genetics; structure; X-ray crystallography
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2022.167527

[Display omitted] •Structures of KRAS/RGL1-Ras association domain complexes.•In-depth structural comparison of Ras/effector complexes.•Structural diversity in the RAS recognition mode of effectors. Ral Guanine Nucleotide Dissociation Stimulator Like 1 (RGL1) is a RAS effector protein that activates Ral GTPase by stimulating nucleotide exchange. Most structures of RAS-effector complexes are for the HRAS isoform; relatively few KRAS-effector structures have been solved, even though KRAS mutations are more frequent in human cancers. We determined crystal structures of KRAS/RGL1-RAS-association (RA) domain complexes and characterized the interaction in solution using nuclear magnetic resonance spectroscopy, size-exclusion chromatography combined with multi-angle light scattering and biolayer interferometry. We report structures of wild-type KRAS and the oncogenic G12V mutant in complex with the RA domain of RGL1 at