The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jesus Ayala-sanmartin - One of the best experts on this subject based on the ideXlab platform.
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Membrane re-arrangements and rippled phase stabilisation by the cell Penetrating peptide Penetratin
Biochimica et Biophysica Acta:Biomembranes, 2016Co-Authors: Claudia Almeida, Antonin Lamaziere, Angélique Filleau, Yohann Corvis, Philippe Espeau, Jesus Ayala-sanmartinAbstract:Cell Penetrating peptides are promising vectors for molecular drug delivery in eukaryotic cells. Despite of their discovery 20 years ago, the mechanisms of peptide membrane crossing are still controversial. The different suggested penetration mechanisms reflect the high sequence and structural diversity of cell Penetrating peptides. The fundamental step for peptide penetration into the cytosol is the crossing of the membrane lipid barrier at the level of the plasma membrane or the endosomes. Therefore, the study of the peptide-lipid interaction is the key for peptide penetration mechanisms understanding. In order to study the changes in lipid organisation induced by the cell Penetrating peptide Penetratin, several experiments by three different physicochemical approaches were performed. X-ray diffraction data shows that Penetratin is able to induce membrane phase separation and lipid rearrangements observed by inter-lipid distances. These changes are accompanied by a temperature stable behaviour of some of the induced membrane domains. The membrane environment fluorescent probe laurdan showed that, in DMPC and DMPC/DMPG membranes, the peptide induces de-packing of lipids. Calorimetric analyses show that Penetratin favours the gel phase to gel-like rippled phase transition. Overall, the data suggest both, that the rippled phase is a heterogeneous structure formed by gel-like and fluid-like coexisting components, and that the Penetratin-induced membrane heterogeneity could be important for membrane destabilisation during cell penetration.
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Metabolic energy-independent mechanism of internalization for the cell Penetrating peptide Penetratin.
BBA - Biochimica et Biophysica Acta, 2012Co-Authors: Ofelia Maniti, Germain Trugnan, Antonin Lamaziere, Elise Blanchard, Jesus Ayala-sanmartinAbstract:Cellular uptake of vector peptides used for internalization of hydrophilic molecules into cells is known to follow two different pathways: direct translocation of the plasma membrane and internalization by endocytosis followed by release into the cytosol. These pathways differ in their energy dependence. The first does not need metabolic energy while the second requires metabolic energy. Herein we used erythrocytes and plasma membrane vesicles to study membrane perturbations induced by the cell Penetrating peptide Penetratin. The results show that cell Penetrating peptides are able to be internalized by two metabolic energy-independent pathways: direct crossing of the plasma membrane and endocytosis-like mechanisms. The last mechanism involves the induction of membrane negative curvature resulting in invaginations that mimic the endosomal uptake in the absence of ATP. This new mechanism called "physical endocytosis" or "self-induced endocytosis" might explain different data concerning the independence or dependence on metabolic energy during cellular uptake and reveals the autonomous capacity of peptides to induce their internalization.
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Lipid domain separation, bilayer thickening and pearling induced by the cell Penetrating peptide Penetratin.
Biochimica et Biophysica Acta - Molecular Cell Research, 2010Co-Authors: Antonin Lamaziere, Germain Trugnan, Ofelia Maniti, Gérard Chassaing, Claude Wolf, Olivier Lambert, Jesus Ayala-sanmartinAbstract:Protein membrane transduction domains are able to translocate through cell membranes. This capacity resulted in new concepts on cell communication and in the design of vectors for internalization of active molecules into cells. Penetratin crosses the plasma membrane by a receptor and metabolic energy-independent mechanism which is at present unknown. A better knowledge of its interaction with phospholipids will help to understand the molecular mechanisms of cell penetration. Here, we investigated the role of lipid composition on Penetratin induced membrane perturbations by X-ray diffraction, microscopy and (31)P-NMR. Penetratin showed the ability to induce phospholipid domain separation, membrane bilayer thickening, formation of vesicles, membrane undulations and tubular pearling. These data demonstrate its capacity to increase membrane curvature and suggest that dynamic phospholipid-Penetratin complexes can be organized in different structural arrangements. These properties and their implications in peptide membrane translocation capacity are discussed.
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Distinct behaviour of the homeodomain derived cell Penetrating peptide Penetratin in interaction with different phospholipids.
PLoS ONE, 2010Co-Authors: Ofelia Maniti, Germain Trugnan, Isabel Alves, Jesus Ayala-sanmartinAbstract:BACKGROUND: Penetratin is a protein transduction domain derived from the homeoprotein Antennapedia. Thereby it is currently used as a cell Penetrating peptide to introduce diverse molecules into eukaryotic cells, and it could also be involved in the cellular export of transcription factors. Moreover, it has been shown that it is able to act as an antimicrobial agent. The mechanisms involved in all these processes are quite controversial. METHODOLOGY/PRINCIPAL FINDINGS: In this article, we report spectroscopic, calorimetric and biochemical data on the Penetratin interaction with three different phospholipids: phosphatidylcholine (PC) and phosphatidylethanolamine (PE) to mimic respectively the outer and the inner leaflets of the eukaryotic plasma membrane and phosphatidylglycerol (PG) to mimic the bacterial membrane. We demonstrate that with PC, Penetratin is able to form vesicle aggregates with no major change in membrane fluidity and presents no well defined secondary structure organization. With PE, Penetratin aggregates vesicles, increases membrane rigidity and acquires an α-helical structure. With PG membranes, Penetratin does not aggregate vesicles but decreases membrane fluidity and acquires a structure with both α-helical and β-sheet contributions. CONCLUSIONS/SIGNIFICANCE: These data from membrane models suggest that the different Penetratin actions in eukaryotic cells (membrane translocation during export and import) and on prokaryotes may result from different peptide and lipid structural arrangements. The data suggest that, for eukaryotic cell penetration, Penetratin does not acquire classical secondary structure but requires a different conformation compared to that in solution.
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Tubular structures in heterogeneous membranes induced by the cell Penetrating peptide Penetratin.
Communicative & integrative biology, 2009Co-Authors: Antonin Lamaziere, Germain Trugnan, Gérard Chassaing, Jesus Ayala-sanmartinAbstract:The delivery of active molecules into cells requires the efficient translocation of the plasma membrane barrier. Penetratin is a promising cell Penetrating peptide is which crosses the cell membrane by a receptor and metabolic energy-independent mechanism. In previous work, we have shown that basic peptides induce membrane invaginations (i.e., tubes formation by induction of negative curvature of membranes) suggesting a new mechanism for cellular uptake of cell Penetrating peptides: “physical endocytosis”. These effects on membrane curvature are favored in pure liquid disordered but not in pure liquid ordered (raft-like) membrane domains. Herein, we present experiments in heterogeneous membranes composed of mixed domains. The results show that Penetratin is able to induce invaginations in membranes in which liquid ordered and liquid disordered membranes coexist. We suggest that Penetratin is able to recruit specific lipids locally forming fluid membrane patches dispersed inside a liquid ordered membrane z...
Istvan M Mandity - One of the best experts on this subject based on the ideXlab platform.
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statin boosted cellular uptake and endosomal escape of Penetratin due to reduced membrane dipole potential
British Journal of Pharmacology, 2021Co-Authors: Gyula Batta, Levente Karpati, Gabriela Fulaneto Henrique, Gabriella Toth, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M MandityAbstract:Background and purpose Cell Penetrating peptides are promising tools for delivery of cargo into cells, but factors limiting or facilitating their cellular uptake are largely unknown. We set out to study the effect of the biophysical properties of the cell membrane on the uptake of Penetratin, a cell Penetrating peptide. Experimental approach Using labeling with pH-insensitive and pH-sensitive dyes, the kinetics of cellular uptake and endo-lysosomal escape of Penetratin were studied by flow cytometry. Key results We report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of Penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. Conclusions and implications These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
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statin boosted cellular uptake and endosomal escape of Penetratin due to reduced membrane dipole potential
Authorea Preprints, 2020Co-Authors: Gyula Batta, Levente Karpati, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M Mandity, Gabriela Fulaneto, Peter NagyAbstract:Since cell Penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of Penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
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statin boosted cellular uptake of Penetratin due to reduced membrane dipole potential
bioRxiv, 2020Co-Authors: Gyula Batta, Levente Karpati, Gabriela Fulaneto Henrique, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M Mandity, Peter NagyAbstract:Abstract Since cell Penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased the release of Penetratin from acidic endocytic compartments in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
Levente Karpati - One of the best experts on this subject based on the ideXlab platform.
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statin boosted cellular uptake and endosomal escape of Penetratin due to reduced membrane dipole potential
British Journal of Pharmacology, 2021Co-Authors: Gyula Batta, Levente Karpati, Gabriela Fulaneto Henrique, Gabriella Toth, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M MandityAbstract:Background and purpose Cell Penetrating peptides are promising tools for delivery of cargo into cells, but factors limiting or facilitating their cellular uptake are largely unknown. We set out to study the effect of the biophysical properties of the cell membrane on the uptake of Penetratin, a cell Penetrating peptide. Experimental approach Using labeling with pH-insensitive and pH-sensitive dyes, the kinetics of cellular uptake and endo-lysosomal escape of Penetratin were studied by flow cytometry. Key results We report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of Penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. Conclusions and implications These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
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statin boosted cellular uptake and endosomal escape of Penetratin due to reduced membrane dipole potential
Authorea Preprints, 2020Co-Authors: Gyula Batta, Levente Karpati, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M Mandity, Gabriela Fulaneto, Peter NagyAbstract:Since cell Penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of Penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
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statin boosted cellular uptake of Penetratin due to reduced membrane dipole potential
bioRxiv, 2020Co-Authors: Gyula Batta, Levente Karpati, Gabriela Fulaneto Henrique, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M Mandity, Peter NagyAbstract:Abstract Since cell Penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased the release of Penetratin from acidic endocytic compartments in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
Szabolcs Tarapcsak - One of the best experts on this subject based on the ideXlab platform.
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statin boosted cellular uptake and endosomal escape of Penetratin due to reduced membrane dipole potential
British Journal of Pharmacology, 2021Co-Authors: Gyula Batta, Levente Karpati, Gabriela Fulaneto Henrique, Gabriella Toth, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M MandityAbstract:Background and purpose Cell Penetrating peptides are promising tools for delivery of cargo into cells, but factors limiting or facilitating their cellular uptake are largely unknown. We set out to study the effect of the biophysical properties of the cell membrane on the uptake of Penetratin, a cell Penetrating peptide. Experimental approach Using labeling with pH-insensitive and pH-sensitive dyes, the kinetics of cellular uptake and endo-lysosomal escape of Penetratin were studied by flow cytometry. Key results We report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of Penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. Conclusions and implications These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
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statin boosted cellular uptake and endosomal escape of Penetratin due to reduced membrane dipole potential
Authorea Preprints, 2020Co-Authors: Gyula Batta, Levente Karpati, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M Mandity, Gabriela Fulaneto, Peter NagyAbstract:Since cell Penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of Penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
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statin boosted cellular uptake of Penetratin due to reduced membrane dipole potential
bioRxiv, 2020Co-Authors: Gyula Batta, Levente Karpati, Gabriela Fulaneto Henrique, Szabolcs Tarapcsak, Tamas Kovacs, Florina Zakany, Istvan M Mandity, Peter NagyAbstract:Abstract Since cell Penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of Penetratin from acidic endo-lysosomal compartments is retarded compared to its cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of Penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased the release of Penetratin from acidic endocytic compartments in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell Penetrating peptides and suggest a clinically relevant way of boosting this process.
Antonin Lamaziere - One of the best experts on this subject based on the ideXlab platform.
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Membrane re-arrangements and rippled phase stabilisation by the cell Penetrating peptide Penetratin
Biochimica et Biophysica Acta:Biomembranes, 2016Co-Authors: Claudia Almeida, Antonin Lamaziere, Angélique Filleau, Yohann Corvis, Philippe Espeau, Jesus Ayala-sanmartinAbstract:Cell Penetrating peptides are promising vectors for molecular drug delivery in eukaryotic cells. Despite of their discovery 20 years ago, the mechanisms of peptide membrane crossing are still controversial. The different suggested penetration mechanisms reflect the high sequence and structural diversity of cell Penetrating peptides. The fundamental step for peptide penetration into the cytosol is the crossing of the membrane lipid barrier at the level of the plasma membrane or the endosomes. Therefore, the study of the peptide-lipid interaction is the key for peptide penetration mechanisms understanding. In order to study the changes in lipid organisation induced by the cell Penetrating peptide Penetratin, several experiments by three different physicochemical approaches were performed. X-ray diffraction data shows that Penetratin is able to induce membrane phase separation and lipid rearrangements observed by inter-lipid distances. These changes are accompanied by a temperature stable behaviour of some of the induced membrane domains. The membrane environment fluorescent probe laurdan showed that, in DMPC and DMPC/DMPG membranes, the peptide induces de-packing of lipids. Calorimetric analyses show that Penetratin favours the gel phase to gel-like rippled phase transition. Overall, the data suggest both, that the rippled phase is a heterogeneous structure formed by gel-like and fluid-like coexisting components, and that the Penetratin-induced membrane heterogeneity could be important for membrane destabilisation during cell penetration.
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Metabolic energy-independent mechanism of internalization for the cell Penetrating peptide Penetratin.
BBA - Biochimica et Biophysica Acta, 2012Co-Authors: Ofelia Maniti, Germain Trugnan, Antonin Lamaziere, Elise Blanchard, Jesus Ayala-sanmartinAbstract:Cellular uptake of vector peptides used for internalization of hydrophilic molecules into cells is known to follow two different pathways: direct translocation of the plasma membrane and internalization by endocytosis followed by release into the cytosol. These pathways differ in their energy dependence. The first does not need metabolic energy while the second requires metabolic energy. Herein we used erythrocytes and plasma membrane vesicles to study membrane perturbations induced by the cell Penetrating peptide Penetratin. The results show that cell Penetrating peptides are able to be internalized by two metabolic energy-independent pathways: direct crossing of the plasma membrane and endocytosis-like mechanisms. The last mechanism involves the induction of membrane negative curvature resulting in invaginations that mimic the endosomal uptake in the absence of ATP. This new mechanism called "physical endocytosis" or "self-induced endocytosis" might explain different data concerning the independence or dependence on metabolic energy during cellular uptake and reveals the autonomous capacity of peptides to induce their internalization.
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Lipid domain separation, bilayer thickening and pearling induced by the cell Penetrating peptide Penetratin.
Biochimica et Biophysica Acta - Molecular Cell Research, 2010Co-Authors: Antonin Lamaziere, Germain Trugnan, Ofelia Maniti, Gérard Chassaing, Claude Wolf, Olivier Lambert, Jesus Ayala-sanmartinAbstract:Protein membrane transduction domains are able to translocate through cell membranes. This capacity resulted in new concepts on cell communication and in the design of vectors for internalization of active molecules into cells. Penetratin crosses the plasma membrane by a receptor and metabolic energy-independent mechanism which is at present unknown. A better knowledge of its interaction with phospholipids will help to understand the molecular mechanisms of cell penetration. Here, we investigated the role of lipid composition on Penetratin induced membrane perturbations by X-ray diffraction, microscopy and (31)P-NMR. Penetratin showed the ability to induce phospholipid domain separation, membrane bilayer thickening, formation of vesicles, membrane undulations and tubular pearling. These data demonstrate its capacity to increase membrane curvature and suggest that dynamic phospholipid-Penetratin complexes can be organized in different structural arrangements. These properties and their implications in peptide membrane translocation capacity are discussed.
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Tubular structures in heterogeneous membranes induced by the cell Penetrating peptide Penetratin.
Communicative & integrative biology, 2009Co-Authors: Antonin Lamaziere, Germain Trugnan, Gérard Chassaing, Jesus Ayala-sanmartinAbstract:The delivery of active molecules into cells requires the efficient translocation of the plasma membrane barrier. Penetratin is a promising cell Penetrating peptide is which crosses the cell membrane by a receptor and metabolic energy-independent mechanism. In previous work, we have shown that basic peptides induce membrane invaginations (i.e., tubes formation by induction of negative curvature of membranes) suggesting a new mechanism for cellular uptake of cell Penetrating peptides: “physical endocytosis”. These effects on membrane curvature are favored in pure liquid disordered but not in pure liquid ordered (raft-like) membrane domains. Herein, we present experiments in heterogeneous membranes composed of mixed domains. The results show that Penetratin is able to induce invaginations in membranes in which liquid ordered and liquid disordered membranes coexist. We suggest that Penetratin is able to recruit specific lipids locally forming fluid membrane patches dispersed inside a liquid ordered membrane z...
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The homeodomain derived peptide Penetratin induces curvature of fluid membrane domains.
PLoS ONE, 2008Co-Authors: Antonin Lamaziere, Germain Trugnan, Gérard Chassaing, Claude Wolf, Olivier Lambert, Jesus Ayala-sanmartinAbstract:BACKGROUND: Protein membrane transduction domains that are able to cross the plasma membrane are present in several transcription factors, such as the homeodomain proteins and the viral proteins such as Tat of HIV-1. Their discovery resulted in both new concepts on the cell communication during development, and the conception of cell Penetrating peptide vectors for internalisation of active molecules into cells. A promising cell Penetrating peptide is Penetratin, which crosses the cell membranes by a receptor and metabolic energy-independent mechanism. Recent works have claimed that Penetratin and similar peptides are internalized by endocytosis, but other endocytosis-independent mechanisms have been proposed. Endosomes or plasma membranes crossing mechanisms are not well understood. Previously, we have shown that basic peptides induce membrane invaginations suggesting a new mechanism for uptake, "physical endocytosis". METHODOLOGY/PRINCIPAL FINDINGS: Herein, we investigate the role of membrane lipid phases on Penetratin induced membrane deformations (liquid ordered such as in "raft" microdomains versus disordered fluid "non-raft" domains) in membrane models. Experimental data show that zwitterionic lipid headgroups take part in the interaction with Penetratin suggesting that the external leaflet lipids of cells plasma membrane are competent for peptide interaction in the absence of net negative charges. NMR and X-ray diffraction data show that the membrane perturbations (tubulation and vesiculation) are associated with an increase in membrane negative curvature. These effects on curvature were observed in the liquid disordered but not in the liquid ordered (raft-like) membrane domains. CONCLUSIONS/SIGNIFICANCE: The better understanding of the internalisation mechanisms of protein transduction domains will help both the understanding of the mechanisms of cell communication and the development of potential therapeutic molecular vectors. Here we showed that the membrane targets for these molecules are preferentially the fluid membrane domains and that the mechanism involves the induction of membrane negative curvature. Consequences on cellular uptake are discussed.