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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 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 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 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 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 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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See detailNanoscale Modification Of Supported Lipid Membranes: Synergetic Effect Of Phospholipase D And Viral Fusion Peptides
El Kirat, K.; Lins, Laurence ULg; Brasseur, Robert ULg et al

in Journal of Biomedical Nanotechnology (2005), 1(1), 1-8

Understanding the molecular bases of biomembrane fusion events is a challenging issue in current biomedical research in view of its involvement in controlling cellular functions and in mediating various ... [more ▼]

Understanding the molecular bases of biomembrane fusion events is a challenging issue in current biomedical research in view of its involvement in controlling cellular functions and in mediating various important diseases. In this study, we used atomic force microscopy (AFM) to address the crucial question as to whether negatively curved lipids influence the ability of a viral fusion peptide to perturb the organization of supported lipid bilayers. To this end, an original approach was developed that makes use of an AFM tip functionalized with phospholipase D (PLD) enzymes to generate in situ small amounts of negatively curved phosphatidic acid (PA) in mixed dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DOPC/DPPC) bilayers. Real-time AFM imaging revealed that this nanomodification dramatically enhanced subsequent interaction with the simian immunodeficiency virus (SIV) fusion peptide. At short incubation time, the SIV peptide induced a 1.9 nm thickness reduction of the DPPC domains, reflecting either interdigitation or fluidification of the lipids. At longer incubation time, these depressed domains transformed into elevated striated domains, protruding one to several nanometers above the bilayer surface. Two complementary experiments, i.e. addition of the peptide onto DOPC/DPPC/DOPA bilayers or onto DOPC/DPPC bilayers pretreated with a PLD solution, confirmed that both PA and SIV peptides are required to induce depressed and striated domains. Accordingly, this is the first time that a high-resolution imaging technique is used to demonstrate that negatively curved lipids affect the membrane activity of fusion peptides. We believe the nanoscale approach presented here, i.e. use of enzyme-functionalized AFM tips to modify lipid bilayers, will find exciting new applications in nanobiotechnology for the design of biomimetic surfaces. [less ▲]

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See detailApolipoprotein L-1 Promotes Trypanosome Lysis By Forming Pores In Lysosomal Membranes
Perez-Morga, David; Vanhollebeke, Benoit; Paturiaux-Hanocq, Françoise et al

in Science (2005), 309(5733), 469-72

Apolipoprotein L-I is the trypanolytic factor of human serum. Here we show that this protein contains a membrane pore-forming domain functionally similar to that of bacterial colicins, flanked by a ... [more ▼]

Apolipoprotein L-I is the trypanolytic factor of human serum. Here we show that this protein contains a membrane pore-forming domain functionally similar to that of bacterial colicins, flanked by a membrane-addressing domain. In lipid bilayer membranes, apolipoprotein L-I formed anion channels. In Trypanosoma brucei, apolipoprotein L-I was targeted to the lysosomal membrane and triggered depolarization of this membrane, continuous influx of chloride, and subsequent osmotic swelling of the lysosome until the trypanosome lysed. [less ▲]

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See detailInteraction of the 106-126 prion peptide with lipid membranes and potential implication for neurotoxicity.
Dupiereux-Fettweis, Ingrid ULg; Zorzi, Willy ULg; Lins, Laurence ULg et al

in Biochemical and Biophysical Research Communications (2005), 331(4), 894-901

Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and beta-sheet rich pathogenic isoform (PrP(SC)) of the ... [more ▼]

Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and beta-sheet rich pathogenic isoform (PrP(SC)) of the cellular prion protein (PrP(C)). In the present work, we were interested to study the mode of prion protein interaction with the membrane using the 106-126 peptide and small unilamellar lipid vesicles as model. As previously demonstrated, we showed by MTS assay that PrP 106-126 induces alterations in the human neuroblastoma SH-SY5Y cell line. We demonstrated for the first time by lipid-mixing assay and by the liposome vesicle leakage test that PrP 106-126, a non-tilted peptide, induces liposome fusion thus a potential cell membrane destabilization, as supported by membrane integrity assay (LDH). By circular dichroism (CD) analysis we showed that the fusogenic property of PrP 106-126 in the presence of liposome is associated with a predominantly beta-sheet structure. These data suggest that the fusogenic property associated with a predominant beta-sheet structure exhibited by the prion peptides contributes to the neurotoxicity of these peptides by destabilizing cellular membranes. The latter might be attached at the membrane surface in a parallel orientation as shown by molecular modeling. [less ▲]

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See detailFusogenic Tilted Peptides Induce Nanoscale Holes In Supported Phosphatidylcholine Bilayers
El Kirat, K.; Lins, Laurence ULg; Brasseur, Robert ULg et al

in Langmuir (2005), 21(7), 3116-21

Tilted peptides are known to insert in lipid bilayers with an oblique orientation, thereby destabilizing membranes and facilitating membrane fusion processes. Here, we report the first direct ... [more ▼]

Tilted peptides are known to insert in lipid bilayers with an oblique orientation, thereby destabilizing membranes and facilitating membrane fusion processes. Here, we report the first direct visualization of the interaction of tilted peptides with lipid membranes using in situ atomic force microscopy (AFM) imaging. Phase-separated supported dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DOPC/DPPC) bilayers were prepared by fusion of small unilamellar vesicles and imaged in buffer solution, in the absence and in the presence of the simian immunodeficiency virus (SIV) peptide. The SIV peptide was shown to induce the rapid appearance of nanometer scale bilayer holes within the DPPC gel domains, while keeping the domain shape unaltered. We attribute this behavior to a local weakening and destabilization of the DPPC domains due to the oblique insertion of the peptide molecules. These results were directly correlated with the fusogenic activity of the peptide as determined using fluorescently labeled DOPC/DPPC liposomes. By contrast, the nontilted ApoE peptide did not promote liposome fusion and did not induce bilayer holes but caused slight erosion of the DPPC domains. In conclusion, this work provides the first direct evidence for the production of stable, well-defined nanoholes in lipid bilayer domains by the SIV peptide, a behavior that we have shown to be specifically related to the tilted character of the peptide. A molecular mechanism underlying spontaneous insertion of the SIV peptide within lipid bilayers and the subsequent removal of bilayer patches is proposed, and its relevance to membrane fusion processes is discussed. [less ▲]

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See detailDetermination Of The Functionality Of Common Apoa5 Polymorphisms
Talmud, Pj.; Palmen, J.; Putt, W. et al

in Journal of Biological Chemistry (2005), 280(31), 28215-20

Common variants of APOA5 have consistently shown association with differences in plasma triglyceride (TG) levels. These single nucleotide polymorphisms (SNPs) fall into three common haplotypes: APOA5*1 ... [more ▼]

Common variants of APOA5 have consistently shown association with differences in plasma triglyceride (TG) levels. These single nucleotide polymorphisms (SNPs) fall into three common haplotypes: APOA5*1, with common alleles at all sites; APOA5*2, with rare alleles of -1131T--> C, -3A--> G, 751G--> T, and 1891T--> C; and APOA5*3, distinguished by the c56C--> G (S19W). Molecular modeling of the apoAV signal peptide (SP) showed an increased angle of insertion (65 degrees ) at the lipid/water interface of Trp-19 SP compared with Ser-19 SP (40 degrees ), predicting reduced translocation. This was confirmed by 50% reduction of Trp-19-encoded SP.secretory alkaline phosphatase (SEAP) fusion protein secreted into the medium from HepG2 cells compared with the Ser-19.SEAP fusion protein (p < 0.002). Considering APOA5*2 SNPs, there was no significant difference in the relative luciferase expression in Huh7 cells transiently transfected with a -1131T construct compared with the -1131C (fragments -1177 to -516 or -1177 to -3). Similarly, for the -3A--> G in the Kozak sequence, in vitro transcription/translation assays and primer extension inhibition assays showed no alternate AUG initiation codon usage, demonstrating that -3A--> G did not influence translation efficiency. Although 1891T--> C in the 3'-untranslated region disrupts a putative Oct-1 transcription factor binding site, when inserted 3' of the luciferase gene the T--> C change demonstrated no significant difference in luciferase expression. Thus, association of APOA5*2 SNPs with TG levels is not due to the individual effects of any of these SNPs, although cooperativity between the SNPs cannot be excluded. Alternatively, the effect on TG levels may reflect the strong linkage disequilibrium with the functional APOC3 SNPs. [less ▲]

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See detailTilted peptides in amyloidogenic proteins
Crowet, Jean-Marc ULg; Brasseur, Robert ULg; Lins, Laurence ULg

Poster (2004, October)

Amyloidogenic proteins are of interest in the study of transconformational processes because they undergo a major conformational change leading to amyloid fibrils formation by a self-assembly of their ... [more ▼]

Amyloidogenic proteins are of interest in the study of transconformational processes because they undergo a major conformational change leading to amyloid fibrils formation by a self-assembly of their misfolded form.   Amyloid fibrils are implicated in several diseases such as Alzheimer, Parkinson or Creutzfeldt-Jakob diseases. Fibrils have varying lengths up to few micrometers, they are unbranched and the individual β strands are oriented perpendicular to the long axis of the fibril. Moreover, the conformational changes induce an increase in the β content. However little is known about the mechanisms of transconformation, the subsequent aggregation and the mechanism toxicity of these proteins. Study of these misfolded proteins, and particularly study of their conformation, is difficult due to their high tendency to aggregate in solution.   Regarding the transconformational mechanisms, it’s interesting to study the potential role of tilted peptides because they possess several properties which could be involved in this process. They can adopt  or β conformation depending on the environment. When helical, they can destabilize the hydrophilic/hydrophobic interface of an organised system. They were notably found in the domain undergoing transconformation in the Aβ protein (Alzheimer’s disease) and in PrP (prion diseases). They could have an important role in the first step of the transconformational process ; their destabilizing properties could also be implicated in the toxicity of these proteins. [less ▲]

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See detailTransferrin-Binding Protein B Of Neisseria Meningitidis: Sequence-Based Identification Of The Transferrin-Binding Site Confirmed By Site-Directed Mutagenesis
Renauld-Mongenie, G.; Lins, Laurence ULg; Krell, T. et al

in Journal of Bacteriology (2004), 186(3), 850-7

A sequence-based prediction method was employed to identify three ligand-binding domains in transferrin-binding protein B (TbpB) of Neisseria meningitidis strain B16B6. Site-directed mutagenesis of ... [more ▼]

A sequence-based prediction method was employed to identify three ligand-binding domains in transferrin-binding protein B (TbpB) of Neisseria meningitidis strain B16B6. Site-directed mutagenesis of residues located in these domains has led to the identification of two domains, amino acids 53 to 57 and 240 to 245, which are involved in binding to human transferrin (htf). These two domains are conserved in an alignment of different TbpB sequences from N. meningitidis and Neisseria gonorrhoeae, indicating a general functional role of the domains. Western blot analysis and BIAcore and isothermal titration calorimetry experiments demonstrated that site-directed mutations in both binding domains led to a decrease or abolition of htf binding. Analysis of mutated proteins by circular dichroism did not provide any evidence for structural alterations due to the amino acid replacements. The TbpB mutant R243N was devoid of any htf-binding activity, and antibodies elicited by the mutant showed strong bactericidal activity against the homologous strain, as well as against several heterologous tbpB isotype I strains. [less ▲]

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See detailDistribution Of Hydrophobic Residues Is Crucial For The Fusogenic Properties Of The Ebola Virus Gp2 Fusion Peptide
Adam, B.; Lins, Laurence ULg; Stroobant, V. et al

in Journal of Virology (2004), 78(4), 2131-6

The lipid-destabilizing properties of the N-terminal domain of the GP2 of Ebola virus were investigated. Our results suggest that the domain of Ebola virus needed for fusion is shorter than that ... [more ▼]

The lipid-destabilizing properties of the N-terminal domain of the GP2 of Ebola virus were investigated. Our results suggest that the domain of Ebola virus needed for fusion is shorter than that previously reported. The fusogenic properties of this domain are related to its oblique orientation at the lipid/water interface owing to an asymmetric distribution of the hydrophobic residues when helical. [less ▲]

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