Structural bases for the involvement of phosphatidylinositol-4,5-bisphosphate in the internalization of the cell-penetrating peptide Penetratin - Sorbonne Université
Journal Articles ACS Chemical Biology Year : 2022

Structural bases for the involvement of phosphatidylinositol-4,5-bisphosphate in the internalization of the cell-penetrating peptide Penetratin

Marine Cosset
  • Function : Author
  • PersonId : 1217481
  • IdRef : 267139764
Ludovic Carlier
Olivier Lequin
Patrick Fuchs

Abstract

Cell-penetrating peptides cross cell membranes through various parallel internalization pathways. Herein, we analyze the role of the negatively charged lipid phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) in the internalization of Penetratin. Contributions of both inner leaflet and outer leaflet pools of PI(4,5)P2 were revealed by quantifying the internalization of Penetratin in cells treated with PI(4,5)P2 binders. Studies on model systems showed that Penetratin has a strong affinity for PI(4,5)P2, and interacts selectively with this lipid, even in the presence of other negatively charged lipids, as demonstrated by affinity photocrosslinking experiments. Differential scanning calorimetry experiments showed that Penetratin induces lateral segregation in PI(4,5)P2-containing liposomes, which was confirmed by coarse-grained molecular dynamics simulations. NMR experiments indicated that Penetratin adopts a stabilized helical conformation in the presence of PI(4,5)P2-containing membranes, with an orientation parallel to the bilayer plane, which was also confirmed by all-atom simulations. NMR and photocrosslinking experiments also suggest a rather shallow insertion of the peptide in the membrane. Put together, our findings suggest that PI(4,5)P2 is a privileged interaction partner for Penetratin and that it plays an important role in Penetratin internalization.
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Dates and versions

hal-03767806 , version 1 (02-09-2022)

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Leïla Bechtella, Edward Chalouhi, Paula Milán Rodríguez, Marine Cosset, Delphine Ravault, et al.. Structural bases for the involvement of phosphatidylinositol-4,5-bisphosphate in the internalization of the cell-penetrating peptide Penetratin. ACS Chemical Biology, 2022, 17 (6), pp.1427-1439. ⟨10.1021/acschembio.1c00974⟩. ⟨hal-03767806⟩
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