Abstract |
The association of K-Ras4B protein with plasma membrane (PM) is required for its signaling activity. Thus, direct inhibition of K-Ras4B-PM interaction could be a potential anti-Ras therapeutic strategy. However, it remains challenging to modulate such protein-PM interaction. Based on Ras isoform-specific PM microdomain localization patterns, we have developed a potent and isoform-selective peptide inhibitor, Memrasin, for detachment of K-Ras4B from the PM. Memrasin is one of the first direct inhibitors of K-Ras4B-PM interaction, and consists of a membrane ld region-binding sequence derived from the C-terminal region of K-Ras4B and an endosome-escape enhancing motif that can aggregate on membrane. It forms peptide-enriched domains in the ld region, abrogates the tethering of K-Ras4B to the PM and accordingly impairs Ras signaling activity, thereby efficiently decreasing the viability of several human lung cancer cells in a dose-responsive and K-Ras dependent manner. Memrasin provides a useful tool for exploring the biological function of K-Ras4B on or off the PM and a potential starting point for further development into anti-Ras therapeutics.
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Authors | Fang-Yi Li, Zhen-Feng Zhang, Stephanie Voss, Yao-Wen Wu, Yu-Fen Zhao, Yan-Mei Li, Yong-Xiang Chen |
Journal | Chemical science
(Chem Sci)
Vol. 11
Issue 3
Pg. 826-832
(Dec 03 2019)
ISSN: 2041-6520 [Print] England |
PMID | 34123058
(Publication Type: Journal Article)
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Copyright | This journal is © The Royal Society of Chemistry. |