Identification of an H-Ras nanocluster disrupting peptide.

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

Communications biology 2024 Jul 09

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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. © 2024. The Author(s).

Citation

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. Identification of an H-Ras nanocluster disrupting peptide. Communications biology. 2024 Jul 09;7(1):837