TAT-RasGAP<sub>317-326</sub> kills cells by targeting inner-leaflet-enriched phospholipids.

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Version: author
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Serval ID
serval:BIB_304AC399FABC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
TAT-RasGAP<sub>317-326</sub> kills cells by targeting inner-leaflet-enriched phospholipids.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Serulla M., Ichim G., Stojceski F., Grasso G., Afonin S., Heulot M., Schober T., Roth R., Godefroy C., Milhiet P.E., Das K., García-Sáez A.J., Danani A., Widmann C.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
15/12/2020
Peer-reviewed
Oui
Volume
117
Number
50
Pages
31871-31881
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
TAT-RasGAP <sub>317-326</sub> is a cell-penetrating peptide-based construct with anticancer and antimicrobial activities. This peptide kills a subset of cancer cells in a manner that does not involve known programmed cell death pathways. Here we have elucidated the mode of action allowing TAT-RasGAP <sub>317-326</sub> to kill cells. This peptide binds and disrupts artificial membranes containing lipids typically enriched in the inner leaflet of the plasma membrane, such as phosphatidylinositol-bisphosphate (PIP <sub>2</sub> ) and phosphatidylserine (PS). Decreasing the amounts of PIP <sub>2</sub> in cells renders them more resistant to TAT-RasGAP <sub>317-326</sub> , while reducing the ability of cells to repair their plasma membrane makes them more sensitive to the peptide. The W317A TAT-RasGAP <sub>317-326</sub> point mutant, known to have impaired killing activities, has reduced abilities to bind and permeabilize PIP <sub>2</sub> - and PS-containing membranes and to translocate through biomembranes, presumably because of a higher propensity to adopt an α-helical state. This work shows that TAT-RasGAP <sub>317-326</sub> kills cells via a form of necrosis that relies on the physical disruption of the plasma membrane once the peptide targets specific phospholipids found on the cytosolic side of the plasma membrane.
Keywords
Animals, CHO Cells, Cell Death/drug effects, Cell Membrane/drug effects, Cell Membrane/metabolism, Cell Membrane/ultrastructure, Cricetulus, GTPase-Activating Proteins/pharmacology, GTPase-Activating Proteins/therapeutic use, HeLa Cells, Humans, Liposomes/metabolism, Liposomes/ultrastructure, Microscopy, Electron, Molecular Dynamics Simulation, Neoplasms/drug therapy, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments/pharmacology, Peptide Fragments/therapeutic use, Phosphatidylinositol 4,5-Diphosphate/metabolism, Phosphatidylserines/metabolism, anticancer peptides, cell-penetrating peptides, membranolytic peptides, phosphatidylserine, phosphoinositides
Pubmed
Web of science
Create date
07/12/2020 15:32
Last modification date
16/07/2021 6:37
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