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Inhibition of K-Ras4B-plasma membrane association with a membrane microdomain-targeting peptide

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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.

Graphical abstract: Inhibition of K-Ras4B-plasma membrane association with a membrane microdomain-targeting peptide

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Publication details

The article was received on 19 Sep 2019, accepted on 28 Nov 2019 and first published on 03 Dec 2019


Article type: Edge Article
DOI: 10.1039/C9SC04726C
Chem. Sci., 2020, Advance Article
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Inhibition of K-Ras4B-plasma membrane association with a membrane microdomain-targeting peptide

    F. Li, Z. Zhang, S. Voss, Y. Wu, Y. Zhao, Y. Li and Y. Chen, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC04726C

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