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Identification of an H-Ras nanocluster disrupting peptide

Authors :
Candy Laura Steffen
Ganesh babu Manoharan
Karolina Pavic
Alejandro Yeste-Vázquez
Matias Knuuttila
Neha Arora
Yong Zhou
Harri Härmä
Anthoula Gaigneaux
Tom N. Grossmann
Daniel Kwaku Abankwa
Source :
Communications Biology, Vol 7, Iss 1, Pp 1-15 (2024)
Publication Year :
2024
Publisher :
Nature Portfolio, 2024.

Abstract

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.

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
23993642
Volume :
7
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Communications Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.824fba21fa7f4eef9a59a3a33f13cb35
Document Type :
article
Full Text :
https://doi.org/10.1038/s42003-024-06523-9