Faculty, Staff and Student Publications
Publication Date
7-9-2024
Journal
Communications Biology
Abstract
Hyperactive Ras signalling is found in most cancers. Ras proteins are only active in membrane nanoclusters, which are therefore potential drug targets. We previously showed that the nanocluster scaffold galectin-1 (Gal1) enhances H-Ras nanoclustering via direct interaction with the Ras binding domain (RBD) of Raf. Here, we establish that the B-Raf preference of Gal1 emerges from the divergence of the Raf RBDs at their proposed Gal1-binding interface. We then identify the L5UR peptide, which disrupts this interaction by binding with low micromolar affinity to the B- and C-Raf-RBDs. Its 23-mer core fragment is sufficient to interfere with H-Ras nanoclustering, modulate Ras-signalling and moderately reduce cell viability. These latter two phenotypic effects may also emerge from the ability of L5UR to broadly engage with several RBD- and RA-domain containing Ras interactors. The L5UR-peptide core fragment is a starting point for the development of more specific reagents against Ras-nanoclustering and -interactors.
Keywords
Humans, Peptides, Proto-Oncogene Proteins p21(ras), Galectin 1, Protein Binding, Signal Transduction, Peptides, Cell signalling
DOI
10.1038/s42003-024-06523-9
PMID
38982284
PMCID
PMC11233548
PubMedCentral® Posted Date
7-9-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes