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TAT-RasGAP317-326 kills cells by targeting inner-leaflet-enriched phospholipids
Marc Serulla1, Gabriel Ichim2, Filip Stojceski3
1Department of Biomedical Sciences, University of Lausanne, 1005 Lausanne, Switzerland.
Abstract:
TAT-RasGAP317-326 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-RasGAP317-326 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 (PIP2) and phosphatidylserine (PS). Decreasing the amounts of PIP2 in cells renders them more resistant to TAT-RasGAP317-326, while reducing the ability of cells to repair their plasma membrane makes them more sensitive to the peptide. The W317A TAT-RasGAP317-326 point mutant, known to have impaired killing activities, has reduced abilities to bind and permeabilize PIP2- 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-RasGAP317-326 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.
Insights
The anticancer peptide TAT-RasGAP317-326 kills cancer cells by physically disrupting the plasma membrane. It targets specific phospholipids like PIP2 and PS, leading to necrosis rather than programmed cell death.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Medicine
Background:
- TAT-RasGAP317-326 is a cell-penetrating peptide with known anticancer and antimicrobial properties.
- Its precise mechanism of cell death induction, distinct from programmed pathways, remained unelucidated.
Purpose of the Study:
- To elucidate the mode of action by which TAT-RasGAP317-326 induces cell death.
- To investigate the role of specific phospholipids and membrane integrity in the peptide's cytotoxic effects.
Main Methods:
- Investigated peptide interaction with artificial membranes containing phosphatidylinositol-bisphosphate (PIP2) and phosphatidylserine (PS).
- Assessed cellular resistance and sensitivity to the peptide based on PIP2 levels and membrane repair capabilities.
- Analyzed the membrane binding, permeabilization, and translocation properties of a W317A point mutant.
Main Results:
- TAT-RasGAP317-326 binds and disrupts artificial membranes enriched in PIP2 and PS.
- Cellular resistance to the peptide is reduced by decreasing PIP2 levels and increased by enhancing membrane repair.
- The W317A mutant shows impaired membrane interaction and translocation, correlating with reduced killing activity.
Conclusions:
- Cell death induced by TAT-RasGAP317-326 is a form of necrosis resulting from physical plasma membrane disruption.
- The peptide's cytotoxicity relies on targeting specific phospholipids (PIP2, PS) on the cytosolic side of the plasma membrane.
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