A BAG-1-inhibitory peptide, GO-Pep, suppresses c-Raf activity in cancer
Creators
- 1. Istanbul Tech Univ, Grad Sch, Mol Biol Genet & Biotechnol, Istanbul, Turkiye
- 2. Cukurova Univ, Inst Nat & Appl Sci, Dept Biol, Adana, Turkiye
- 3. Acibadem Univ, Inst Hlth Sci, Dept Med Biotechnol, Istanbul, Turkiye
- 4. Acibadem Univ, Grad Sch Nat & Appl Sci, Dept Mol Biol & Genet, Istanbul, Turkiye
- 5. Dokuz Eylul Univ, Fac Med, Izmir Biomed & Genome Ctr, Izmir, Turkiye
- 6. Acibadem Univ, Fac Engn & Nat Sci, Dept Biomed Engn, Istanbul, Turkiye
Description
BAG-1 interacts with multiple partners, particularly with c-Raf, and promotes cancer cell survival. Hence, modulating the BAG-1-associated interactions with novel inhibitors could provide benefit for cancer therapy. Using HDX-MS, we first demonstrate the higher-order structure of BAG-1S and identify a potential "druggable" site on its BAG domain. An LC-MS/MS-coupled cell-free binding experiment is then used to map the BAG-1S:c-Raf interface, uncovering a 20-amino acid-length region of BAG-1S that is most likely to interact with c-Raf. Site-directed mutagenesis experiments reveal that K149 and L156 are hot spots for BAG-1S:c-Raf interaction, and their substitutions with alanine attenuate the survival of MCF-7 cells. We then show that a peptide derived from the BAG-1S-interacting c-Raf region hinders BAG domain-associated partners. The peptide, engineered with a cell-penetrating peptide motif, can penetrate cells, and it induces apoptosis in cancer cells. The anticancer activity of the peptide might lead to improved treatments for BAG-1-overexpressed and/or MAPK-driven tumors.
Files
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Files
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