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60. A mechanism for the rearrangement of unsymmetrical tetradentate (N2O2) ligands bound to manganese(III): the isolation and crystal structure of a manganese(III) complex containing a ten-membered cis-chelated ring

Author

Bermejo, Manuel R., primary, Deibe, Ana Garcia, additional, Rey, Manuel, additional, Sanmartin, Jesus, additional, Sousa, Antonio, additional, Aurangzeb, Nadeem, additional, Hulme, Charlotte E., additional, McAuliffe, Charles A., additional, Pritchard, Robin G., additional, Watkinson, Michael, additional, and Helliwell, Madeleine, additional

Published
1994
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61. Isolation of a remarkably stable hydrogen bonded dimeric manganese(II) complex, [Mn(L)(OH2)]2(Me2SO)2from the reduction of a manganese(III) Schiff base complex [L = the dianion of N,N′-bis(3-bromo-5-nitrosalicylidene)-1,2-diamino-(2-methyl)ethane]

Author

Bermejo, Manuel R., primary, Garcia-Deibe, Ana, additional, Sanmartin, Jesus, additional, Sousa, Antonio, additional, Aurangzeb, Nadeem, additional, Hulme, Charlotte E., additional, McAuliffe, Charles A., additional, Pritchard, Robin G., additional, and Watkinson, Michael, additional

Published
1994
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62. Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II.

Author

Jie liu, Rothermund, Christy A., Ayala-Sanmartin, Jesus, and Vishwanatha, Jamboor K.

Subjects
ANNEXINS, PROSTATE cancer, GLUTAMIC acid, MONOMERS, GENETIC mutation, PHOSPHORYLATION, CELL proliferation
Abstract

Background: Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II. Results: Annexin II localized in the nucleus is phosphorylated, and the appearance of nuclear phosphorylated annexin II is cell cycle dependent, indicating that phosphorylation may play a role in nuclear entry, retention or export of annexin II. By exogenous expression of annexin II in the annexin II-null LNCaP cells, we show that wild-type annexin II is excluded from the nucleus, whereas the NES mutant annexin II localizes in both the nucleus and cytoplasm. Nuclear retention of annexin II results in reduced cell proliferation and increased doubling time of cells. Expression of annexin II, both wild type and NES mutant, causes morphological changes of the cells. By site-specific substitution of glutamic acid in the place of serines 11 and 25 in the N-terminus, we show that simultaneous phosphorylation of both serines 11 and 25, but not either one alone, prevents nuclear localization of annexin II. Conclusion: Our data show that nuclear annexin II is phosphorylated in a cell cycle-dependent manner and that substitution of serines 11 and 25 inhibit nuclear entry of annexin II. Aberrant accumulation of nuclear annexin II retards proliferation of LNCaP cells. [ABSTRACT FROM AUTHOR]

Published
2003
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63. Modulation by Ca[sup 2+] and by Membrane Binding of the Dynamics of Domain III of...

Author

Ayala-Sanmartin, Jesus and Vincent, Michel

Subjects
*ANNEXINS, *CALCIUM
Abstract

Studies the modulation of the local structure and dynamics of domain III of annexin 2 in both the monomeric and heterotetrameric forms by calcium and by membrane binding using time-resolved fluorescence intensity. Effect of calcium binding to p36 and p90 on the excited-state lifetime distribution.

Published
2000
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66. Cholesterol regulates membrane binding and aggregation by annexin 2 at submicromolar Ca 2+ concentration

Author

Louise-Anne Pradel, Jesus Ayala-Sanmartin, Jean-Pierre Henry, Biologie cellulaire et moléculaire de la sécrétion (BCMS), Centre National de la Recherche Scientifique (CNRS), This work was supported by the Centre National de la Recherche Scientifique (UPR 1929) and the Association pour la Recherche sur le Cancer (contract 9275)., and Ayala-Sanmartin, Jesus

Subjects
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Biophysics, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Biochemistry, Exocytosis, Membrane Lipids, chemistry.chemical_compound, Annexin, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Chromaffin granule, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], membrane binding, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Annexin A2, Cyclodextrins, Liposome, Dose-Response Relationship, Drug, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Cholesterol, beta-Cyclodextrins, aggregation, cholesterol, chromaffin granules, Intracellular Membranes, Annexin 2, Cell Biology, Phosphatidylserine, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, EGTA, Membrane, chemistry, Liposomes, Calcium, lipids (amino acids, peptides, and proteins), Protein Binding
Abstract

International audience; Annexin 2 is a member of the annexin family which has been implicated in calcium-regulated exocytosis. This contention is largely based on Ca(2+)-dependent binding of the protein to anionic phospholipids. However, annexin 2 was shown to be associated with chromaffin granules in the presence of EGTA. A fraction of this bound annexin 2 was released by methyl-beta-cyclodextrin, a reagent which depletes cholesterol from membranes. Restoration of the cholesterol content of chromaffin granule membranes with cholesterol/methyl-beta-cyclodextrin complexes restored the Ca(2+)-independent binding of annexin 2. The binding of both, monomeric and tetrameric forms of annexin 2 was also tested on liposomes of different composition. In the absence of Ca(2+), annexin 2, especially in its tetrameric form, bound to liposomes containing phosphatidylserine, and the addition of cholesterol to these liposomes increased the binding. Consistent with this observation, liposomes containing phosphatidylserine and cholesterol were aggregated by the tetrameric form of annexin 2 at submicromolar Ca(2+) concentrations. These results indicate that the lipid composition of membranes, and especially their cholesterol content, is important in the control of the subcellular localization of annexin 2 in resting cells, at low Ca(2+) concentration. Annexin 2 might be associated with membrane domains enriched in phosphatidylserine and cholesterol.

Published
2001
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67. Basic cell penetrating peptides induce plasma membrane positive curvature, lipid domain separation and protein redistribution

Author

Jesus Ayala-Sanmartin, Ofelia Maniti, Hong-Rong Piao, Génie Enzymatique, Membrane Biomimétique et Assemblages Supramoléculaires (GEMBAS), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des matériaux et du génie physique (LMGP ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National Polytechnique de Grenoble (INPG)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), and Ayala-Sanmartin, Jesus

Subjects
plasma membrane 2 Abbreviations: CPP, Molecular Sequence Data, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Cell-Penetrating Peptides, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], 010402 general chemistry, 01 natural sciences, Biochemistry, Exocytosis, Polar membrane, Cell Penetratin Peptide, 03 medical and health sciences, Membrane Lipids, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Membrane fluidity, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Integral membrane protein, Basic peptides, 030304 developmental biology, 0303 health sciences, Microscopy, Confocal, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Peripheral membrane protein, Cell Membrane, membrane rolling, Membrane Proteins, Biological membrane, Cell Biology, 0104 chemical sciences, Cell biology, Protein Structure, Tertiary, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, membrane domains, Membrane curvature, membrane curvature, Plasma Membrane Sphere, Carrier Proteins, Elasticity of cell membranes
Abstract

International audience; : Basic cell penetrating peptides are tools for molecular cellular internalization of non membrane permeable molecules. Their uptake mechanisms involve energy-dependent and energy-independent pathways such as endocytosis, direct translocation or physical endocytosis. These mechanisms are ruled by both, the peptides physicochemical properties and structure and by the membrane lipids characteristics and organisation. Herein we used plasma membrane spheres and membrane models to study the membrane perturbations induced by three arginine-rich cell penetrating peptides. Nona-arginine (R9) and the amphipathic peptide RWRRWWRRW (RW9) induced positive membrane curvature in the form of buds and membrane tubes. Membranous tubes underwent rolling resulting in formation of multilamellar membrane particles at the surface of the plasma membrane spheres. The amphipathic peptides RW9 and RRWRRWWRRWWRRWRR (RW16) provoked lipid and membrane associated protein domain separation as well as changes in membrane fluidity and cholesterol redistribution. These data suggest that membrane domains separation and the formation of multilamellar membranous particles would be involved in arginine-rich cell penetrating peptides internalization.

Published
2013
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68. Lipid domain separation, bilayer thickening and pearling induced by the cell penetrating peptide penetratin

Author

Germain Trugnan, Olivier Lambert, Antonin Lamaziere, Jesus Ayala-Sanmartin, Claude Wolf, Gérard Chassaing, Ofelia Maniti, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Centre National de la Recherche Scientifique (CNRS)-École Supérieure Chimie Physique Électronique de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Polytech'Paris-UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université Sciences et Technologies - Bordeaux 1-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Centre National de la Recherche Scientifique (CNRS), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Ayala-Sanmartin, Jesus, Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
PG, Lipid Bilayers, Cell-Penetrating Peptides, MLV, 01 natural sciences, Biochemistry, Membrane fluidity, Physical endocytosis 2 Abbreviations Chol, Large unilamellar vesicle, GUV, Lipid bilayer, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 0303 health sciences, Lipid phase separation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, Peripheral membrane protein, SM, SAXS, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Membrane curvature, PC, PE, Penetratin, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], giant unilamellar vesicle, Membrane lipids, small angle X-ray scattering, Biophysics, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Biology, 010402 general chemistry, Polar membrane, 03 medical and health sciences, Membrane Lipids, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Sphingomyeline, 030304 developmental biology, LUV, Membrane thickening, L-α-Phosphatidylcholine, nona-arginine peptide, Physical endocytosis, cholesterol, Biological membrane, Cell Biology, [CHIM.ORGA] Chemical Sciences/Organic chemistry, 0104 chemical sciences, cell penetrating peptide, multilamellar vesicle, Membrane pearling, R9, L-α-Phosphatidyl-DL-glycerol, L-α- Phosphatidyl-ethanolamine, Carrier Proteins, CPP, Elasticity of cell membranes
Abstract

International audience; 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.

Published
2010
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69. Distinct behaviour of the homeodomain derived cell penetrating peptide penetratin in interaction with different phospholipids

Author

Isabel D. Alves, Ofelia Maniti, Germain Trugnan, Jesus Ayala-Sanmartin, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des matériaux et du génie physique (LMGP ), Institut National Polytechnique de Grenoble (INPG)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Ayala-Sanmartin, Jesus

Subjects
Protein Folding, Lipid Bilayers, lcsh:Medicine, Cell-Penetrating Peptides, Biochemistry, 01 natural sciences, Protein Structure, Secondary, Cell membrane, chemistry.chemical_compound, Drug Discovery, Molecular Cell Biology, Membrane fluidity, lcsh:Science, Lipid bilayer, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Protein secondary structure, Phospholipids, 0303 health sciences, Multidisciplinary, Calorimetry, Differential Scanning, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, Vesicle, Phosphatidylglycerols, Lipids, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, medicine.anatomical_structure, Membrane, Spectrophotometry, Cytochemistry, Antennapedia Homeodomain Protein, Phosphatidylcholines, Membranes and Sorting, Research Article, Protein Binding, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Biophysics, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Biology, 010402 general chemistry, 03 medical and health sciences, medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Phosphatidylethanolamine, Phosphatidylethanolamines, Cell Membrane, lcsh:R, Membrane Proteins, Proteins, Protein Structure, Tertiary, 0104 chemical sciences, Transmembrane Proteins, chemistry, Cell-penetrating peptide, lcsh:Q, Carrier Proteins, Peptides
Abstract

International audience; 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 a-helical structure. With PG membranes, penetratin does not aggregate vesicles but decreases membrane fluidity and acquires a structure with both a-helical and b–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.

Published
2010
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70. The homeodomain derived peptide Penetratin induces curvature of fluid membrane domains

Author

Germain Trugnan, Claude Wolf, Jesus Ayala-Sanmartin, Gérard Chassaing, Antonin Lamaziere, Olivier Lambert, Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Ayala-Sanmartin, Jesus

Subjects
Vesicle-associated membrane protein 8, Magnetic Resonance Spectroscopy, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Biophysics, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, lcsh:Medicine, Cell-Penetrating Peptides, Biology, 010402 general chemistry, Models, Biological, 01 natural sciences, Exocytosis, Membrane Lipids, 03 medical and health sciences, Membrane Microdomains, X-Ray Diffraction, Scattering, Radiation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Science, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Integral membrane protein, 030304 developmental biology, 0303 health sciences, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cell Membrane, Peripheral membrane protein, lcsh:R, Biological membrane, Cell Biology, Membrane transport, Lipids, Endocytosis, Protein Structure, Tertiary, 0104 chemical sciences, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Protein Transport, Membrane protein, tat Gene Products, Human Immunodeficiency Virus, lcsh:Q, Carrier Proteins, Peptides, Research Article, Biotechnology, Elasticity of cell membranes
Abstract

International audience; 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.

Published
2008
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71. Non-Metabolic Membrane Tubulation and Permeability Induced by Bioactive Peptides

Author

Jesus Ayala-Sanmartin, Germain Trugnan, Fabienne Burlina, Antonin Lamaziere, Claude Wolf, Gérard Chassaing, Université Pierre et Marie Curie - Paris 6 (UPMC), Inflammation intestinale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Ayala-Sanmartin, Jesus

Subjects
Lipid Bilayers, Drug Evaluation, Preclinical, lcsh:Medicine, Peptide, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Cell-Penetrating Peptides, Substance P, Vesicle lumen, 01 natural sciences, Membrane Fusion, Protein Structure, Secondary, Cricetinae, Lipid bilayer, lcsh:Science, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Peptide sequence, Annexin A2, chemistry.chemical_classification, 0303 health sciences, Drug Carriers, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Membrane tubulation, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Chemistry, Vesicle, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Hydrophobic and Hydrophilic Interactions, Research Article, Biotechnology, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Membrane lipids, Green Fluorescent Proteins, Molecular Sequence Data, Biophysics, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, CHO Cells, 010402 general chemistry, Endocytosis, Models, Biological, Permeability, 03 medical and health sciences, Membrane Lipids, Cricetulus, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, 030304 developmental biology, lcsh:R, Cell Biology, 0104 chemical sciences, lcsh:Q, Carrier Proteins, Peptides
Abstract

International audience; Background. Basic cell-penetrating peptides are potential vectors for therapeutic molecules and display antimicrobial activity. The peptide-membrane contact is the first step of the sequential processes leading to peptide internalization and cell activity. However, the molecular mechanisms involved in peptide-membrane interaction are not well understood and are frequently controversial. Herein, we compared the membrane activities of six basic peptides with different size, charge density and amphipaticity: Two cell-penetrating peptides (penetratin and R9), three amphipathic peptides and the neuromodulator substance P. Methodology/Principal Findings. Experiments of X ray diffraction, video-microscopy of giant vesicles, fluorescence spectroscopy, turbidimetry and calcein leakage from large vesicles are reported. Permeability and toxicity experiments were performed on cultured cells. The peptides showed differences in bilayer thickness perturbations, vesicles aggregation and local bending properties which form lipidic tubular structures. These structures invade the vesicle lumen in the absence of exogenous energy. Conclusions/Significance. We showed that the degree of membrane permeabilization with amphipathic peptides is dependent on both peptide size and hydrophobic nature of the residues. We propose a model for peptide-induced membrane perturbations that explains the differences in peptide membrane activities and suggests the existence of a facilitated ''physical endocytosis,'' which represents a new pathway for peptide cellular internalization.

Published
2007
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72. [Transduction peptides: structural-functional analyses in model membranes].

Author

Lamazière A, Chassaing G, Trugnan G, and Ayala-Sanmartin J

Subjects
Biopolymers, Carrier Proteins physiology, Cell-Penetrating Peptides, Drug Compounding, Fluoresceins metabolism, Liposomes, Membrane Lipids, Peptides chemistry, Permeability, Phosphatidylcholines, Phosphatidylglycerols, Plant Proteins chemistry, Spectrometry, Fluorescence, Structure-Activity Relationship, Substance P physiology, Membranes, Artificial, Peptides physiology, Plant Proteins physiology
Abstract

Peptide-membrane interaction is the first step required for peptide cell internalization. In this paper we studied the interactions of substance P, Penetratin and an amphiphilic 16mer (RL16) peptide in two different model membranes, giant unilamellar vesicles and large unilamellar vesicles. Penetratin was able to induce the formation of tubes inside the giant vesicles without changes in membrane permeability. On the contrary, RL16 induced the disruption of giant vesicles and the permeabilization of large vesicles. Substance P showed none of these effects.

Published
2006
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73. Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II.

Author

Liu J, Rothermund CA, Ayala-Sanmartin J, and Vishwanatha JK

Subjects
Active Transport, Cell Nucleus, Amino Acid Substitution, Annexin A2 genetics, Annexin A2 metabolism, Cell Cycle, Cell Division, Cell Line, Tumor, Cell Nucleus chemistry, Cytoplasm metabolism, Glutamic Acid genetics, Humans, Karyopherins metabolism, Male, Mutation, Phosphorylation, Prostatic Neoplasms pathology, Protein Sorting Signals, Serine genetics, Exportin 1 Protein, Annexin A2 chemistry, Annexin A2 physiology, Cell Nucleus metabolism, Prostatic Neoplasms metabolism, Receptors, Cytoplasmic and Nuclear
Abstract

Background: Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II., Results: Annexin II localized in the nucleus is phosphorylated, and the appearance of nuclear phosphorylated annexin II is cell cycle dependent, indicating that phosphorylation may play a role in nuclear entry, retention or export of annexin II. By exogenous expression of annexin II in the annexin II-null LNCaP cells, we show that wild-type annexin II is excluded from the nucleus, whereas the NES mutant annexin II localizes in both the nucleus and cytoplasm. Nuclear retention of annexin II results in reduced cell proliferation and increased doubling time of cells. Expression of annexin II, both wild type and NES mutant, causes morphological changes of the cells. By site-specific substitution of glutamic acid in the place of serines 11 and 25 in the N-terminus, we show that simultaneous phosphorylation of both serines 11 and 25, but not either one alone, prevents nuclear localization of annexin II., Conclusion: Our data show that nuclear annexin II is phosphorylated in a cell cycle-dependent manner and that substitution of serines 11 and 25 inhibit nuclear entry of annexin II. Aberrant accumulation of nuclear annexin II retards proliferation of LNCaP cells.

Published
2003
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