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See detailDetermination Of The Minimal Fusion Peptide Of Hiv, Siv And Blv Fusion Glycoproteins
Lorin, A.; Charloteaux, Benoît ULg; Lins, Laurence ULg et al

in Peptides For Youth - the Proceedings of the 20th American Peptidesymposium (2009), 611

The entry of enveloped viruses into target cells requires the fusion between the viral envelope and the target cell membrane. In the case of many viruses like HIV, SIV and BLV, the fusion is mediated by ... [more ▼]

The entry of enveloped viruses into target cells requires the fusion between the viral envelope and the target cell membrane. In the case of many viruses like HIV, SIV and BLV, the fusion is mediated by class 1 fusion glycoproteins located on the viral envelope. These fusion glycoproteins contain a region at their N-terminal extremity called the “fusion peptide”, which interact with the target membrane. Many mutagenesis studies showed that this region is required for mediating membrane fusion [1]. Moreover, synthetic peptides corresponding to the fusion peptide of many glycoproteins induce membrane fusion in vitro. Despite the large number of studies on synthetic fusion peptides, the region necessary and sufficient to induce optimal membrane fusion is not known. To determine this minimal fusion peptide, we used the “tilted peptide” theory. According to this theory, a helical peptide inserting obliquely into membranes induces fusion [2]. Moreover, the more tilted the peptide is, the more important the fusion is. Then, we postulate that the minimal fusion peptide corresponds to the shortest helical fragment able to insert into the membrane with an angle close to 45°. This peptide was predicted using the IMPALA algorithm, which allow to predict peptide-membrane interactions [3]. Fusogenicity of this peptide was then assessed in liposome lipid-mixing and leakage assays and compared to the fusogenicity of smaller and longer peptides to check the validity of the prediction. This methodology was used to determine successfully the minimal fusion peptide of three viruses, HIV, SIV and BLV. [less ▲]

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See detailThe Minimal Fusion Peptide Of Simian Immunodeficiency Virus Corresponds To The 11 First Residues Of Gp32
Lorin, A.; Lins, Laurence ULg; Stroobant, V. et al

in Journal of Peptide Science (2008), 14(4), 423-8

We had previously predicted successfully the minimal fusion peptides (FPs) of the human immunodeficiency virus 1 (HIV-1) gp41 and the bovine leukemia virus (BLV) gp30 using an original approach based on ... [more ▼]

We had previously predicted successfully the minimal fusion peptides (FPs) of the human immunodeficiency virus 1 (HIV-1) gp41 and the bovine leukemia virus (BLV) gp30 using an original approach based on the obliquity/fusogenicity relationship of tilted peptides. In this paper, we have used the same method to predict the shortest FP capable of inducing optimal fusion in vitro of the simian immunodeficiency virus (SIV) mac isolate and of other SIVs and human immunodeficiency virus (HIV-2) isolates. In each case, the 11-residue-long peptide was predicted as the minimal FP. For the SIV mac isolate, liposome lipid-mixing and leakage assays confirmed that this peptide is the shortest peptide inducing optimal fusion in vitro, being therefore the minimal FP. These results are another piece of evidence that the tilted properties of FPs are important for the fusion process and that our method can be used to predict the minimal FPs of other viruses. [less ▲]

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See detailDetermination Of The Minimal Fusion Peptide Of Bovine Leukemia Virus Gp30
Lorin, A.; Lins, Laurence ULg; Stroobant, V. et al

in Biochemical and Biophysical Research Communications (2007), 355(3), 649-53

In this study, we determined the minimal N-terminal fusion peptide of the gp30 of the bovine leukemia virus on the basis of the tilted peptide theory. We first used molecular modelling to predict that the ... [more ▼]

In this study, we determined the minimal N-terminal fusion peptide of the gp30 of the bovine leukemia virus on the basis of the tilted peptide theory. We first used molecular modelling to predict that the gp30 minimal fusion peptide corresponds to the 15 first residues. Liposome lipid-mixing and leakage assays confirmed that the 15-residue long peptide induces fusion in vitro and that it is the shortest peptide inducing optimal fusion since longer peptides destabilize liposomes to the same extent but not shorter ones. The 15-residue long peptide can thus be considered as the minimal fusion peptide. The effect of mutations reported in the literature was also investigated. Interestingly, mutations related to glycoproteins unable to induce syncytia in cell-cell fusion assays correspond to peptides predicted as non-tilted. The relationship between obliquity and fusogenicity was also confirmed in vitro for one tilted and one non-tilted mutant peptide. [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-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 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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