References of "Brasseur, Robert"
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See detailDecrease Of Elastic Moduli Of Dopc Bilayers Induced By A Macrolide Antibiotic, Azithromycin
Fa, N.; Lins, Laurence ULg; Courtoy, Pj. et al

in Biochimica et Biophysica Acta-Biomembranes (2007), 1768(7), 1830-8

The elastic properties of membrane bilayers are key parameters that control its deformation and can be affected by pharmacological agents. Our previous atomic force microscopy studies revealed that the ... [more ▼]

The elastic properties of membrane bilayers are key parameters that control its deformation and can be affected by pharmacological agents. Our previous atomic force microscopy studies revealed that the macrolide antibiotic, azithromycin, leads to erosion of DPPC domains in a fluid DOPC matrix [A. Berquand, M. P. Mingeot-Leclercq, Y. F. Dufrene, Real-time imaging of drug-membrane interactions by atomic force microscopy, Biochim. Biophys. Acta 1664 (2004) 198-205.]. Since this observation could be due to an effect on DOPC cohesion, we investigated the effect of azithromycin on elastic properties of DOPC giant unilamellar vesicles (GUVs). Microcinematographic and morphometric analyses revealed that azithromycin addition enhanced lipid membranes fluctuations, leading to eventual disruption of the largest GUVs. These effects were related to change of elastic moduli of DOPC, quantified by the micropipette aspiration technique. Azithromycin decreased both the bending modulus (k(c), from 23.1+/-3.5 to 10.6+/-4.5 k(B)T) and the apparent area compressibility modulus (K(app), from 176+/-35 to 113+/-25 mN/m). These data suggested that insertion of azithromycin into the DOPC bilayer reduced the requirement level of both the energy for thermal fluctuations and the stress to stretch the bilayer. Computer modeling of azithromycin interaction with DOPC bilayer, based on minimal energy, independently predicted that azithromycin (i) inserts at the interface of phospholipid bilayers, (ii) decreases the energy of interaction between DOPC molecules, and (iii) increases the mean surface occupied by each phospholipid molecule. We conclude that azithromycin inserts into the DOPC lipid bilayer, so as to decrease its cohesion and to facilitate the merging of DPPC into the DOPC fluid matrix, as observed by atomic force microscopy. These investigations, based on three complementary approaches, provide the first biophysical evidence for the ability of an amphiphilic antibiotic to alter lipid elastic moduli. This may be an important determinant for drug: lipid interactions and cellular pharmacology. [less ▲]

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See detailThe Biologically Important Surfactin Lipopeptide Induces Nanoripples In Supported Lipid Bilayers
Brasseur, Robert ULg; Braun, N.; El Kirat, K. et al

in Langmuir (2007), 23(19), 9769-72

Under specific conditions, lipid membranes form ripple phases with intriguing nanoscale undulations. Here, we show using in situ atomic force microscopy (AFM) that the biologically important surfactin ... [more ▼]

Under specific conditions, lipid membranes form ripple phases with intriguing nanoscale undulations. Here, we show using in situ atomic force microscopy (AFM) that the biologically important surfactin lipopeptide induces nanoripples of 30 nm periodicity in dipalmitoyl phosphatidylcholine (DPPC) bilayers at 25 degrees (i.e. well below the pretransition temperature of DPPC). Whereas most undulations formed the classical straight orientation with characteristic angle changes of 120 degrees , some of them also displayed unusual circular orientations. Strikingly, ripple structures were formed at 15% surfactin but were rarely or never observed at 5 and 30% surfactin, emphasizing the important role played by the surfactin concentration. Theoretical simulations corroborated the AFM data by revealing the formation of stable surfactin/lipid assemblies with positive curvature. [less ▲]

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See detailProbing The Interaction Forces Between Hydrophobic Peptides And Supported Lipid Bilayers Using Afm
Andre, G.; Brasseur, Robert ULg; Dufrene, Yf.

in Journal of Molecular Recognition (2007), 20(6), 538-45

Despite the vast body of literature that has accumulated on tilted peptides in the past decade, direct information on the forces that drive their interaction with lipid membranes is lacking. Here, we ... [more ▼]

Despite the vast body of literature that has accumulated on tilted peptides in the past decade, direct information on the forces that drive their interaction with lipid membranes is lacking. Here, we attempted to use atomic force microscopy (AFM) to explore the interaction forces between the Simian immunodeficiency virus peptide and phase-separated supported bilayers composed of various lipids, i.e. dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, dioleoylphosphatidic acid and dipalmitoylphosphatidylethanolamine. Histidine-tagged peptides were attached onto AFM tips terminated with nitrilotriacetate and tri(ethylene glycol) groups, an approach expected to ensure optimal exposure of the C-terminal hydrophobic domain. Force-distance curves recorded between peptide-tips and the different bilayer domains always showed a long-range repulsion upon approach and a lack of adhesion upon retraction, in marked contrast with the hydrophobic nature of the peptide. To explain this unexpected behaviour, we suggest a mechanism in which lipids are pulled out from the bilayer due to strong interactions with the peptide-tip, in agreement with the very low force needed to extract lipids from supported bilayers. [less ▲]

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See detailMode Of Membrane Interaction And Fusogenic Properties Of A De Novo Transmembrane Model Peptide Depend On The Length Of The Hydrophobic Core
Lorin, A.; Charloteaux, Benoît ULg; Fridmann-Sirkis, Y. et al

in Journal of Biological Chemistry (2007), 282(25), 18388-96

Model peptides composed of alanine and leucine residues are often used to mimic single helical transmembrane domains. Many studies have been carried out to determine how they interact with membranes ... [more ▼]

Model peptides composed of alanine and leucine residues are often used to mimic single helical transmembrane domains. Many studies have been carried out to determine how they interact with membranes. However, few studies have investigated their lipid-destabilizing effect. We designed three peptides designated KALRs containing a hydrophobic stretch of 14, 18, or 22 alanines/leucines surrounded by charged amino acids. Molecular modeling simulations in an implicit membrane model as well as attenuated total reflection-Fourier transform infrared analyses show that KALR is a good model of a transmembrane helix. However, tryptophan fluorescence and attenuated total reflection-Fourier transform infrared spectroscopy indicate that the extent of binding and insertion into lipids increases with the length of the peptide hydrophobic core. Although binding can be directly correlated to peptide hydrophobicity, we show that insertion of peptides into a membrane is determined by the length of the peptide hydrophobic core. Functional studies were performed by measuring the ability of peptides to induce lipid mixing and leakage of liposomes. The data reveal that whereas KALR14 does not destabilize liposomal membranes, KALR18 and KALR22 induce 40 and 50% of lipid-mixing, and 65 and 80% of leakage, respectively. These results indicate that a transmembrane model peptide can induce liposome fusion in vitro if it is long enough. The reasons for the link between length and fusogenicity are discussed in relation to studies of transmembrane domains of viral fusion proteins. We propose that fusogenicity depends not only on peptide insertion but also on the ability of peptides to destabilize the two leaflets of the liposome membrane. [less ▲]

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See detailLipid-Destabilizing Properties Of The Hydrophobic Helices H8 And H9 From Colicin E1
Lins, Laurence ULg; El Kirat, K.; Charloteaux, Benoît ULg et al

in Molecular Membrane Biology (2007), 24(5-6), 419-30

Colicins are toxic proteins produced by Escherichia coli that must cross the membrane to exert their activity. The lipid insertion of their pf domain is linked to a conformational change which enables the ... [more ▼]

Colicins are toxic proteins produced by Escherichia coli that must cross the membrane to exert their activity. The lipid insertion of their pf domain is linked to a conformational change which enables the penetration of a hydrophobic hairpin. They provide useful models to more generally study insertion of proteins, channel formation and protein translocation in and across membranes. In this paper, we study the lipid-destabilizing properties of helices H8 and H9 forming the hydrophobic hairpin of colicin E1. Modelling analysis suggests that those fragments behave like tilted peptides. The latter are characterized by an asymmetric distribution of their hydrophobic residues when helical. They are able to interact with a hydrophobic/hydrophilic interface (such as a lipid membrane) and to destabilize the organized system into which they insert. Fluorescence techniques using labelled liposomes clearly show that H9, and H8 to a lesser extent, destabilize lipid particles, by inducing fusion and leakage. AFM assays clearly indicate that H8 and especially H9 induce membrane fragilization. Holes in the membrane are even observed in the presence of H9. This behaviour is close to what is seen with viral fusion peptides. Those results suggest that the peptides could be involved in the toroidal pore formation of colicin E1, notably by disturbing the lipids and facilitating the insertion of the other, more hydrophilic, helices that will form the pore. Since tilted, lipid-destabilizing fragments are also common to membrane proteins and to signal sequences, we suggest that tilted peptides should have an ubiquitous role in the mechanism of insertion of proteins into membranes. [less ▲]

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See detailPeculiar hydrophobic properties of the 67-78 fragment of α-synuclein are responsible for membrane destabilization and neurotoxicity
Crowet, Jean-Marc ULg; Lins, Laurence ULg; Dupiereux-Fettweis, Ingrid ULg et al

Poster (2006, December 18)

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ... [more ▼]

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ago, tilted peptides have been detected in two other amyloidogenic proteins : the amyloid β peptide involved in Alzheimer’s disease, and the PrP protein linked to Creuztfeldt-Jakob’s disease. Tilted peptides are short protein fragments that adopt an oblique orientation when inserted into biological membranes. Tilted peptides are able to destabilize membranes. In this study, we predicted by sequence analysis and molecular modelling that the 67-78 fragment of α-synuclein is a tilted peptide. Like most of them, the α-syn 67-78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. A mutant designed by molecular modelling to decrease the destabilizing properties of the peptide was shown to be significantly less fusogenic. The neuronal toxicity was studied using human neuroblastoma cells and we demonstrated that the α-syn 67-78 peptide induces neurotoxicity. In conclusion, we have identified a tilted peptide in α-synuclein which could be involved in the toxicity induced during amyloidogenesis of α-synuclein. [less ▲]

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See detailPBP5 complementation of a PBP3 deficiency in Enterococcus hirae
Leimanis, S.; Hoyez, N.; Hubert, S et al

in Journal of Bacteriology (2006), 188(17), 6298-6307

The low susceptibility of enterococci to beta-lactams is due to the activity of the low-affinity penicillin-binding protein 5 (PBP5). One important feature of PBP5 is its ability to substitute for most ... [more ▼]

The low susceptibility of enterococci to beta-lactams is due to the activity of the low-affinity penicillin-binding protein 5 (PBP5). One important feature of PBP5 is its ability to substitute for most, if not all, penicillin-binding proteins when they are inhibited. That substitution activity was analyzed in Enterococcus hirae SL2, a mutant whose pbp5 gene was interrupted by the nisRK genes and whose PBP3 synthesis was submitted to nisin induction. Noninduced SL2 cells were unable to divide except when plasmid-borne pbp5 genes were present, provided that the PBP5 active site was functional. Potential protein-protein interaction sites of the PBP5 N-terminal module were mutagenized by site-directed mutagenesis. The T-167-L-184 region (designated site D) appeared to be an essential intramolecular site needed for the stability of the protein. Mutations made in the two globular domains present in the N-terminal module indicated that they were needed for the suppletive activity. The P-197-N-209 segment (site E) in one of these domains seemed to be particularly important, as single and double mutations reduced or almost completely abolished, respectively, the action of PBP5. [less ▲]

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See detailThe Siv Tilted Peptide Induces Cylindrical Reverse Micelles In Supported Lipid Bilayers
El Kirat, K.; Dufrene, Yf.; Lins, Laurence ULg et al

in Biochemistry (2006), 45(30), 9336-41

Elucidation of the molecular mechanism leading to biomembrane fusion is a challenging issue in current biomedical research in view of its involvement in controlling cellular functions and in mediating ... [more ▼]

Elucidation of the molecular mechanism leading to biomembrane fusion is a challenging issue in current biomedical research in view of its involvement in controlling cellular functions and in mediating various important diseases. According to the generally admitted stalk mechanism described for membrane fusion, negatively curved lipids may play a central role during the early steps of the process. In this study, we used atomic force microscopy (AFM) to address the crucial question of whether negatively curved lipids influence the interaction of the simian immunodeficiency virus (SIV) fusion peptide with model membranes. To this end, dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DOPC/DPPC) bilayers containing 0.5 mol % dioleoylphosphatidic acid (DOPA) were incubated with the SIV peptide and imaged in real time using AFM. After a short incubation time, we observed a 1.9 nm reduction in the thickness of the DPPC domains, reflecting either interdigitation or fluidization of lipids. After longer incubation times, these depressed DPPC domains evolved into elevated domains, composed of nanorod structures protruding several nanometers above the bilayer surface and attributed to cylindrical reverse micelles. Such DOPC/DPPC/DOPA bilayer modifications were never observed with nontilted peptides. Accordingly, this is the first time that AFM reveals the formation of cylindrical reverse micelles in lipid bilayers promoted by fusogenic peptides. [less ▲]

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See detailIn Vitro Characterization Of The Homogalacturonan-Binding Domain Of The Wall-Associated Kinase Wak1 Using Site-Directed Mutagenesis
Decreux, Annabelle ULg; Thomas, Annick ULg; Spies, B. et al

in Phytochemistry (2006), 67(11), 1068-79

Wall-associated kinase 1--WAK1 is a transmembrane protein containing a cytoplasmic Ser/Thr kinase domain and an extracellular domain in contact with the pectin fraction of the plant cell wall in ... [more ▼]

Wall-associated kinase 1--WAK1 is a transmembrane protein containing a cytoplasmic Ser/Thr kinase domain and an extracellular domain in contact with the pectin fraction of the plant cell wall in Arabidopsis thaliana (L.) HEYNH. In a previous paper [Decreux, A., Messiaen, J., 2005. Wall-associated kinase WAK1 interacts with cell wall pectins in a calcium-induced conformation. Plant Cell Physiol. 46, 268-278], we showed that a recombinant peptide expressed in yeast corresponding to amino acids 67-254 of the extracellular domain of WAK1 specifically interacts with commercial non-methylesterified homogalacturonic acid, purified homogalacturonans from Arabidopsis and oligogalacturonides in a calcium-induced conformation. In this report, we used a receptor binding domain sequence-based prediction method to identify four putative binding sites in the extracellular domain of WAK1, in which cationic amino acids were selected for substitution by site-directed mutagenesis. Interaction studies between mutated forms of WAK1 and homogalacturonans allowed us to identify and confirm at least five specific amino acids involved in the interaction with homogalacturonan dimers and multimers. The presence of this homogalacturonan-binding domain within the extracellular domain of WAK1 is discussed in terms of cell wall architecture and signal transduction. [less ▲]

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See detailLipid-Destabilising Properties Of A Peptide With Structural Plasticity
Lorin, A.; Thomas, Annick ULg; Stroobant, V. et al

in Chemistry and Physics of Lipids (2006), 141(1-2), 185-96

The Chameleon peptide (Cham) is a peptide designed from two regions of the GB1 protein, one folded as an alpha-helix and the other as a beta structure. Depending on the environment, the Cham peptide ... [more ▼]

The Chameleon peptide (Cham) is a peptide designed from two regions of the GB1 protein, one folded as an alpha-helix and the other as a beta structure. Depending on the environment, the Cham peptide adopts an alpha or a beta conformation when inserted in different locations of GB1. This environment dependence is also observed for tilted peptides. These short protein fragments, able to destabilise organised system, are mainly folded in beta structure in water and in alpha helix in a hydrophobic environment, like the lipid bilayer. In this paper, we tested whether the Cham peptide can be qualified as a tilted peptide. For this, we have compared the properties of Cham peptide (hydrophobicity, destabilising properties, conformation) to those of tilted peptides. The results suggest that Cham is a tilted peptide. Our study, together the presence of tilted fragments in transconformational proteins, suggests a relationship between tilted peptides and structural lability. [less ▲]

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See detail"De novo" design of peptides with specific lipid-binding properties
Lins, Laurence ULg; Charloteaux, Benoît ULg; Heinen, C. et al

in Biophysical Journal (2006), 90(2), 470-479

In this study, we describe an in silico method to design peptides that can be made of non-natural amino acids and elicit specific membrane-interacting properties. The originality of the method holds in ... [more ▼]

In this study, we describe an in silico method to design peptides that can be made of non-natural amino acids and elicit specific membrane-interacting properties. The originality of the method holds in the capacities developed to design peptides from any non-natural amino acids as easily as from natural ones, and to test the structure stability by an angular dynamics rather than the currently-used molecular dynamics. The goal of this study was to design a non-natural tilted peptide. Tilted peptides are short protein fragments able to destabilize lipid membranes and characterized by an asymmetric distribution of hydrophobic residues along their helix structure axis. The method is based on the random generation of peptides and their election on three main criteria: mean hydrophobicity and the presence of at least one polar residue; tilted insertion at the level of the acyl chains of lipids of a membrane; and conformational stability in that hydrophobic phase. From 10,000,000 randomly-generated peptides, four met all the criteria. One was synthesized and tested for its lipid-destabilizing properties. Biophysical assays showed that the "de novo" peptide made of non-natural amino acids is helical either in solution or intolipids as tested by Fourier transform infrared spectroscopy and is able to induce liposome fusion. These results are in agreement with the calculations andvalidate the theoretical approach. [less ▲]

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See detailProlactin/growth hormone-derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis
Nguyen, Ngoc-Quynh-Nhu ULg; Tabruyn, Sébastien ULg; Lins, Laurence ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(39), 14319-14324

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short ... [more ▼]

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis. [less ▲]

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See detailAnti-Hemostatic Effects Of A Serpin From The Saliva Of The Tick Ixodes Ricinus
Prevot, Pp.; Adam, B.; Boudjeltia, Kz. et al

in Journal of Biological Chemistry (2006), 281(36), 26361-9

Serpins (serine protease inhibitors) are a large family of structurally related proteins found in a wide variety of organisms, including hematophagous arthropods. Protein analyses revealed that Iris ... [more ▼]

Serpins (serine protease inhibitors) are a large family of structurally related proteins found in a wide variety of organisms, including hematophagous arthropods. Protein analyses revealed that Iris, previously described as an immunomodulator secreted in the tick saliva, is related to the leukocyte elastase inhibitor and possesses serpin motifs, including the reactive center loop (RCL), which is involved in the interaction between serpins and serine proteases. Only serine proteases were inhibited by purified recombinant Iris (rIris), whereas mutants L339A and A332P were found devoid of any protease inhibitory activity. The highest Ka was observed with human leukocyte-elastase, suggesting that elastase-like proteases are the natural targets of Iris. In addition, mutation M340R completely changed both Iris substrate specificity and affinity. This likely identified Met-340 as amino acid P1 in the RCL. The effects of rIris and its mutants were also tested on primary hemostasis, blood clotting, and fibrinolysis. rIris increased platelet adhesion, the contact phase-activated pathway of coagulation, and fibrinolysis times in a dose-dependent manner, whereas rIris mutant L339A affected only platelet adhesion. Taken together, these results indicate that Iris disrupts coagulation and fibrinolysis via the anti-proteolytic RCL domain. One or more other domains could be responsible for primary hemostasis inhibition. To our knowledge, this is the first ectoparasite serpin that interferes with both hemostasis and the immune response. [less ▲]

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See detailThe N-terminal 12 residue long peptide of HIV gp41 is the minimal peptide sufficient to induce significant T-cell-like membrane destabilization in vitro.
Charloteaux, Benoît ULg; Lorin, A.; Crowet, Jean-Marc ULg et al

in Journal of molecular biology (2006), 359(3), 597-609

Here, we predicted the minimal N-terminal fragment of gp41 required to induce significant membrane destabilization using IMPALA. This algorithm is dedicated to predict peptide interaction with a membrane ... [more ▼]

Here, we predicted the minimal N-terminal fragment of gp41 required to induce significant membrane destabilization using IMPALA. This algorithm is dedicated to predict peptide interaction with a membrane. We based our prediction of the minimal fusion peptide on the tilted peptide theory. This theory proposes that some protein fragments having a peculiar distribution of hydrophobicity adopt a tilted orientation at a hydrophobic/hydrophilic interface. As a result of this orientation, tilted peptides should disrupt the interface. We analysed in silico the membrane-interacting properties of gp41 N-terminal peptides of different length derived from the isolate BRU and from an alignment of 710 HIV strains available on the Los Alamos National Laboratory. Molecular modelling results indicated that the 12 residue long peptide should be the minimal fusion peptide. We then assayed lipid-mixing and leakage of T-cell-like liposomes with N-terminal peptides of different length as first challenge of our predictions. Experimental results confirmed that the 12 residue long peptide is necessary and sufficient to induce membrane destabilization to the same extent as the 23 residue long fusion peptide. In silico analysis of some fusion-incompetent mutants presented in the literature further revealed that they cannot insert into a modelled membrane correctly tilted. According to this work, the tilted peptide model appears to explain at least partly the membrane destabilization properties of HIV fusion peptide. [less ▲]

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See detailThe N-Terminal Juxtamembranous Domain Of Kcnq1 Is Critical For Channel Surface Expression - Implications In The Romano-Ward Lqt1 Syndrome
Dahimene, S.; Alcolea, S.; Naud, P. et al

in Circulation Research (2006), 99(10), 1076-83

arrhythmias in newborn children and adolescents but the cellular mechanisms involved in this dramatic issue remain, however, to be discovered. Here, we analyzed the trafficking of a series of N-terminal ... [more ▼]

arrhythmias in newborn children and adolescents but the cellular mechanisms involved in this dramatic issue remain, however, to be discovered. Here, we analyzed the trafficking of a series of N-terminal truncation mutants and identified a critical trafficking motif of KCNQ1. This determinant is located in the juxtamembranous region preceding the first transmembrane domain of the protein. Three mutations (Y111C, L114P and P117L) implicated in inherited Romano-Ward LQT1 syndrome, are embedded within this domain. Reexpression studies in both COS-7 cells and cardiomyocytes showed that the mutant proteins fail to exit the endoplasmic reticulum. KCNQ1 subunits harboring Y111C or L114P exert a dominant negative effect on the wild-type KCNQ1 subunit by preventing plasma membrane trafficking of heteromultimeric channels. The P117L mutation had a less pronounced effect on the trafficking of heteromultimeric channels but altered the kinetics of the current. Furthermore, we showed that the trafficking determinant in KCNQ1 is structurally and functionally conserved in other KCNQ channels and constitutes a critical trafficking determinant of the KCNQ channel family. Computed structural predictions correlated the potential structural changes introduced by the mutations with impaired protein trafficking. In conclusion, our studies unveiled a new role of the N-terminus of KCNQ channels in their trafficking and its implication in severe forms of LQT1 syndrome. [less ▲]

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See detailRational Design Of Complementary Peptides To The Beta Amyloid 29-42 Fusion Peptide: An Application Of Pepdesign
Decaffmeyer, Marc; Lins, Laurence ULg; Charloteaux, Benoît ULg et al

in Biochimica et Biophysica Acta-Biomembranes (2006), 1758(3), 320-7

Peptides in solution currently exist under several conformations; an equilibrium which varies with solvent polarity. Despite or because of this structure versatility, peptides can be selective biological ... [more ▼]

Peptides in solution currently exist under several conformations; an equilibrium which varies with solvent polarity. Despite or because of this structure versatility, peptides can be selective biological tools: they can adapt to a target, vary conformation with solvents and so on. These capacities are crucial for cargo carriers. One promising way of using peptides in biotechnologies is to decipher their medium-sequence-structure-function relationships and one approach is molecular modelling. Only few "in silico" methods of peptide design are described in the literature. Most are used in support of experimental screening of peptide libraries. However, the way they are made does not teach us much for future researches. In this paper, we describe an "in silico" method (PepDesign) which starts by analysing the native interaction of a peptide with a target molecule in order to define which points are important. From there, a modelling protocol for the design of 'better' peptides is set. The PepDesign procedure calculates new peptides fulfilling the hypothesis, tests the conformational space of these peptides in interaction with the target by angular dynamics and goes up to the selection of the best peptide based on the analysis of complex structure properties. Experimental biological assays are finally used to test the selected peptides, hence to validate the approach. Applications of PepDesign are wide because the procedure will remain similar irrespective of the target which can be a protein, a drug or a nucleic acid. In this paper, we describe the design of peptides which binds to the fusogenic helical form of the C-terminal domain of the Abeta peptide (Abeta29-42). [less ▲]

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