Details

Autor(en) / Beteiligte

• Serulla, Marc
• Ichim, Gabriel
• Stojceski, Filip
• Grasso, Gianvito
• Afonin, Sergii
• Heulot, Mathieu
• Schober, Tim
• Roth, Robyn
• Godefroy, Cédric
• Milhiet, Pierre-Emmanuel
• Das, Kushal
• García-Sáez, Ana J.
• Danani, Andrea
• Widmann, Christian

Titel

TAT-RasGAP317-326 kills cells by targeting inner-leaflet–enriched phospholipids

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2020-12, Vol.117 (50), p.31871-31881

Ort / Verlag

Washington: National Academy of Sciences

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.