Structural Bases for the Involvement of Phosphatidylinositol-4,5-bisphosphate in the Internalization of the Cell-Penetrating Peptide Penetratin.

Autor: Bechtella L; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Chalouhi E; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Milán Rodríguez P; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Cosset M; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Ravault D; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Illien F; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Sagan S; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Carlier L; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Lequin O; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France., Fuchs PFJ; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France.; Université de Paris, UFR Sciences du Vivant, 75013 Paris, France., Sachon E; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France.; Sorbonne Université, Mass Spectrometry Sciences Sorbonne Université, MS3U platform, UFR 926, UFR 927, Paris 75005, France., Walrant A; Laboratoire des Biomolécules, LBM, Sorbonne Université, École normale supérieure, PSL University, CNRS, 75005 Paris, France.
Jazyk: angličtina
Zdroj: ACS chemical biology [ACS Chem Biol] 2022 Jun 17; Vol. 17 (6), pp. 1427-1439. Date of Electronic Publication: 2022 May 24.
DOI: 10.1021/acschembio.1c00974
Abstrakt: 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)P 2 ) in the internalization of Penetratin. Contributions of both inner leaflet and outer leaflet pools of PI(4,5)P 2 were revealed by quantifying the internalization of Penetratin in cells treated with PI(4,5)P 2 binders. Studies on model systems showed that Penetratin has a strong affinity for PI(4,5)P 2 and interacts selectively with this lipid, even in the presence of other negatively charged lipids, as demonstrated by affinity photo-crosslinking experiments. Differential scanning calorimetry experiments showed that Penetratin induces lateral segregation in PI(4,5)P 2 -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)P 2 -containing membranes, with an orientation parallel to the bilayer plane, which was also confirmed by all-atom simulations. NMR and photo-crosslinking experiments also suggest a rather shallow insertion of the peptide in the membrane. Put together, our findings suggest that PI(4,5)P 2 is a privileged interaction partner for Penetratin and that it plays an important role in Penetratin internalization.
Databáze: MEDLINE
Externí odkaz: