TY - JOUR
T1 - Identification of an H-Ras nanocluster disrupting peptide
AU - Steffen, Candy Laura
AU - Manoharan, Ganesh babu
AU - Pavic, Karolina
AU - Yeste-Vázquez, Alejandro
AU - Knuuttila, Matias
AU - Arora, Neha
AU - Zhou, Yong
AU - Härmä, Harri
AU - Gaigneaux, Anthoula
AU - Grossmann, Tom N.
AU - Abankwa, Daniel Kwaku
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/7/9
Y1 - 2024/7/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85198060540&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/38982284/
U2 - 10.1038/s42003-024-06523-9
DO - 10.1038/s42003-024-06523-9
M3 - Article
C2 - 38982284
AN - SCOPUS:85198060540
SN - 2399-3642
VL - 7
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 837
ER -