[en] Class I fusion glycoproteins of viruses are involved in the fusion between viral envelope and cell membrane. A region located in the N-terminal domain of these glycoproteins, called the fusion peptide, is essential for fusion. Fusion peptides are able to induce by themselves in vitro membrane fusion. In this paper, we review the properties of those peptides related to their fusogenicity, in particular the correlation existing between their ability to insert obliquely in membranes and fusogenicity. This relation notably allows predicting successfully the minimal region of some fusion peptides sufficient to induce significant in vitro fusion. The notion of obliquity and fusogenicity is discussed in terms of the existing proposed mechanisms for viral fusion.
Earp, L. J.; Delos, S. E.; Park, H. E.; White, J. M. The many mechanisms of viral membrane fusion proteins. Curr. Top. Microbiol. Immunol., 2005, 285(1), 25-66.
Skehel, J. J.; Wiley, D. C. Receptor binding and membrane fusion in virus entry: The influenza hemagglutinin. An. Rev. Biochem., 2000, 69(3), 531-569.
Harrison, S. C. Mechanism of membrane fusion by viral envelope proteins. Virus Struct. Assembly, 2005, 64(2), 231-261.
Colman, P. M.; Lawrence, M. C. The structural biology of type I viral membrane fusion. Nature Rev. Mol. Cell Biol., 2003, 4(4), 309-319.
Carr, C. M.; Kim, P. S. A Spring-Loaded Mechanism for the Conformational Change of Influenza Hemagglutinin. Cell, 1993, 73(4), 823-832.
Carr, C. M.; Chaudhry, C.; Kim, P. S. Influenza hemagglutinin is spring-loaded by a metastable native conformation. Proc. Natl. Acad. Sci. USA, 1997, 94(26), 14306-14313.
White, J. M. Membrane-Fusion. Science, 1992, 258(5084), 917-924.
Gallaher, W. R. Detection of A Fusion Peptide Sequence in the Transmembrane Protein of Human-Immunodeficiency-Virus. Cell, 1987, 50(3), 327-328.
Durell, S. R.; Martin, I.; Ruysschaert, J. M.; Shai, Y.; Blumenthal, R. What studies of fusion peptides tell us about viral envelope glycoprotein-mediated membrane fusion. Mol. Membr. Biol., 1997, 14(3), 97-112.
Bosch, M. L.; Earl, P. L.; Fargnoli, K.; Picciafuoco, S.; Giombini, F.; Wongstaal, F.; Franchini, G. Identification of the Fusion Peptide of Primate Immunodeficiency Viruses. Science, 1989, 244(4905), 694-697.
Freed, E. O.; Myers, D. J.; Risser, R. Characterization of the Fusion Domain of the Human-Immunodeficiency-Virus Type-1 Envelope Glycoprotein Gp41. Proc. Natl. Acad. Sci. USA, 1990, 87(12), 4650-4654.
Durrer, P.; Galli, C.; Hoenke, S.; Corti, C.; Gluck, R.; Vorherr, T.; Brunner, J. H+-induced membrane insertion of influenza virus hemagglutinin involves the HA2 amino-terminal fusion peptide but not the coiled coil region. J. Biol. Chem., 1996, 271(23), 13417-13421.
Peisajovich, S. G.; Shai, Y. Viral fusion proteins: multiple regions contribute to membrane fusion. Biochim. Biophys. Acta-Biomembranes, 2003, 1614(1), 122-129.
Weissenhorn, W.; Dessen, A.; Harrison, S. C.; Skehel, J. J.; Wiley, D. C. Atomic structure of the ectodomain from HIV-1 gp41. Nature, 1997, 387(6631), 426-430.
Nieva, J. L.; Agirre, A. Are fusion peptides a good model to study viral cell fusion? Biochim. Biophys. Acta-Biomembranes, 2003, 1614(1), 104-115.
Martin, I.; Ruysschaert, J. M.; Epand, R. M. Role of the N-terminal peptides of viral envelope proteins in membrane fusion. Adv. Drug Deliv. Rev., 1999, 38(3), 233-255.
Epand, R. M. Fusion peptides and the mechanism of viral fusion. Biochim. Biophys. Acta, 2003, 1614(1), 116-121.
Brasseur, R.; Lorge, P.; Goormaghtigh, E.; Ruysschaert, J. M.; Espion, D.; Burny, A. The mode of insertion of the paramyxovirus F1 N-terminus into lipid matrix, an initial step in host cell/virus fusion. Virus Genes, 1988, 1(4), 325-332.
Brasseur, R.; Vandenbranden, M.; Cornet, B.; Burny, A.; Ruysschaert, J. M. Orientation Into the Lipid Bilayer of An Asymmetric Amphipathic Helical Peptide Located at the N-Terminus of Viral Fusion Proteins. Biochim. Biophys. Acta, 1990, 1029(2), 267-273.
Efremov, R. G.; Nolde, D. E.; Volynsky, P. E.; Chernyavsky, A. A.; Dubovskii, P. V.; Arseniev, A. S. Factors important for fusogenic activity of peptides: molecular modeling study of analogs of fusion peptide of influenza virus hemagglutinin. FEBS Lett., 1999, 462(1-2), 205-210.
Lins, L.; Charloteaux, B.; Thomas, A.; Brasseur, R. Computational study of lipid-destabilizing protein fragments: Towards a comprehensive view of tilted peptides. Prot. Struct. Funct. Genet., 2001, 44(4), 435-447.
Voneche, V.; Portelle, D.; Kettmann, R.; Willems, L.; Limbach, K.; Paoletti, E.; Ruysschaert, J. M.; Burny, A.; Brasseur, R. Fusogenic Segments of Bovine Leukemia-Virus and Simian Immunodeficiency Virus Are Interchangeable and Mediate Fusion by Means of Oblique Insertion in the Lipid Bilayer of Their Target-Cells. Proc. Natl. Acad. Sci. USA, 1992, 89(9), 3810-3814.
Adam, B.; Lins, L.; Stroobant, V.; Thomas, A.; Brasseur, R. Distribution of hydrophobic residues is crucial for the fusogenic properties of the Ebola virus GP2 fusion peptide. J. Virol, 2004, 78(4), 2131-2136.
Martin, I.; Schaal, H.; Scheid, A.; Ruysschaert, J. M. Lipid membrane fusion induced by the human immunodeficiency virus type 1 gp41 N-terminal extremity is determined by its orientation in the lipid bilayer. J. Virol., 1996, 70(1), 298-304.
Martin, I.; Dubois, M. C.; Defrisequertain, F.; Saermark, T.; Burny, A.; Brasseur, R.; Ruysschaert, J. M. Correlation Between Fusogenicity of Synthetic Modified Peptides Corresponding to the Nh2-Terminal Extremity of Simian Immunodeficiency Virus Gp32 and Their Mode of Insertion Into the Lipid Bilayer-An Infrared-Spectroscopy Study. J. Virol., 1994, 68(2), 1139-1148.
Luneberg, J.; Martin, I.; Nussler, F.; Ruysschaert, J. M.; Herrmann, A. Structure and Topology of the Influenza-Virus Fusion Peptide in Lipid Bilayers. J. Biol. Chem., 1995, 270(46), 27606-27614.
Bradshaw, J. P.; Darkes, M. J. M.; Harroun, T. A.; Katsaras, J.; Epand, R. M. Oblique membrane insertion of viral fusion peptide probed by neutron diffractions. Biochemistry, 2000, 39(22), 6581-6585.
Han, X.; Bushweller, J. H.; Cafiso, D. S.; Tamm, L. K. Membrane structure and fusion-triggering conformational change of the fusion domain from influenza hemagglutinin. Nat. Struct. Biol., 2001, 8(8), 715-720.
Lai, A. L.; Park, H.; White, J. M.; Tamm, L. K. Fusion peptide of influenza hemagglutinin requires a fixed angle boomerang structure for activity. J. Biol. Chem., 2006, 281(9), 5760-5770.
Brasseur, R.; Pillot, T.; Lins, L.; Vandekerckhove, J.; Rosseneu, M. Peptides in membranes: Tipping the balance of membrane stability. Tibs, 1997, 22(5), 167-171.
Lins, L.; Flore, C.; Chapelle, L.; Talmud, P. J.; Thomas, A.; Brasseur, R. Lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III. Prot. Eng., 2002, 15(6), 513-520.
Ravault, S.; Soubias, O.; Saurel, O.; Thomas, A.; Brasseur, R.; Milon, A. Fusogenic Alzheimer's peptide fragment A beta (29-42) in interaction with lipid bilayers: Secondary structure, dynamics, and specific interaction with phosphatidyl ethanolamine polar heads as revealed by solid-state NMR. Prot. Sci., 2005, 14(5), 1181-1189.
Pillot, T.; Goethals, M.; Vanloo, B.; Talussot, C.; Brasseur, R.; Vandekerckhove, J.; Rosseneu, M.; Lins, L. Fusogenic properties of the C-terminal domain of the Alzheimer beta-amyloid peptide. J. Biol. Chem., 1996, 271(46), 28757-28765.
Pillot, T.; Lins, L.; Goethals, M.; Vanloo, B.; Baert, J.; Vandekerckhove, J.; Rosseneu, M.; Brasseur, R. The 118-135 peptide of the human prion protein forms amyloid fibrils and induces liposome fusion. J. Mol. Biol., 1997, 274(3), 381-393.
Crowet, J. M.; Lins, L.; Dupiereux, I.; Elmoualija, B.; Lorin, A.; Charloteaux, B.; Stroobant, V.; Heinen, E.; Brasseur, R. Tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity. Prot. Struct. Funt. Genet., 2007, 68(4), 936-947.
Lins, L.; Brasseur, R. Tilted peptides: a structural motif involved in protein membrane insertion? J. Pept. Sci., 2008, 14(4), 416-422.
Peuvot, J.; Schanck, A.; Lins, L.; Brasseur, R. Are the fusion processes involved in birth, life and death of the cell depending on tilted insertion of peptides into membranes? J. Theor. Biol., 1999, 198(2), 173-181.
Lins, L.; Charloteaux, B.; Heinen, C.; Thomas, A.; Brasseur, R. "De novo" design of peptides with specific lipid-binding properties. Biophys. J., 2006, 90(2), 470-479.
Brasseur, R. Tilted peptides: a motif for membrane destabilization (hypothesis). Mol. Membrane Biol., 2000, 17(1), 31-40.
Brasseur, R. Differentiation of lipid-associating helices by use of three-dimensional molecular hydrophobicity potential calculations. J. Biol. Chem., 1991, 266(24), 16120-16127.
Harris, F.; Wallace, J.; Phoenix, D. A. Use of hydrophobic moment plot methodology to aid the identification of oblique orientated alpha-helices. Mol. Membrane Biol., 2000, 17(4), 201-207.
Lorin, A.; Thomas, A.; Stroobant, V.; Brasseur, R.; Lins, L. Lipiddestabilising properties of a peptide with structural plasticity. Chem. Phys. Lipids, 2006, 141(1-2), 185-196.
Decout, A.; Labeur, C.; Vanloo, B.; Goethals, M.; Vandekerckhove, J.; Brasseur, R.; Rosseneu, M. Contribution of the hydrophobicity gradient to the secondary structure and activity of fusogenic peptides. Mol. Membrane Biol., 1999, 16(3), 237-246.
Pillot, T.; Lins, L.; Goethals, M.; Vanloo, B.; Baert, J.; Vandekerckhove, J.; Rosseneu, M.; Brasseur, R. The 118-135 peptide lot the human prion protein forms amyloid fibrils and induces liposome fusion. J. Mol. Biol., 1997, 274(3), 381-393.
Lambert, G.; Decout, A.; Vanloo, B.; Rouy, D.; Duverger, N.; Kalopissis, A.; Vadekerckhove, J.; Chambaz, J.; Brasseur, R.; Rosseneu, M. The C-terminal helix of human apolipoprotein AII promotes the fusion of unilamellar liposomes and displaces apolipoprotein AI from high-density lipoproteins. Eur. J. Biochem., 1998, 253(1), 328-338.
Horth, M.; Lambrecht, B.; Khim, M. C. L.; Bex, F.; Thiriart, C.; Ruysschaert, J. M.; Burny, A.; Brasseur, R. Theoretical and Functional-Analysis of the Siv Fusion Peptide. EMBO J., 1991, 10(10), 2747-2755.
Kamath, S.; Wong, T. C. Membrane structure of the human immunodeficiency virus gp41 fusion domain by molecular dynamics simulation. Biophys. J., 2002, 83(1), 135-143.
Epand, R. M. Membrane fusion. Biosci. Rep., 2000, 20(6), 435-441.
Siegel, D. P. The modified stalk mechanism of lamellar/inverted phase transitions and its implications for membrane fusion. Biophys. J., 1999, 76(1), 291-313.
Siegel, D. P. Stalk Structures As Intermediates in Membrane-Fusion and Bilayer Nonbilayer Phase-Transitions. Biophys. J., 1993, 64(2), A186-A186.
El Kirat, K.; Dufrene, Y. F.; Lins, L.; Brasseur, R. The SIV tilted peptide induces cylindrical reverse micelles in supported lipid bilayers. Biochem, 2006, 45(30), 9336-9341.
Lins, L.; Decaffmeyer, M.; Thomas, A.; Brasseur, R. Relationships between the orientation and the structural properties of peptides and their membrane interactions. Biochim. Biophys. Acta, 2008, 1778(7-8), 1537-1544.
Martin, I.; Defrisequertain, F.; Decroly, E.; Vandenbranden, M.; Brasseur, R.; Ruysschaert, J. M. Orientation and Structure of the Nh2-Terminal Hiv-1 Gp41 Peptide in Fused and Aggregated Liposomes. Biochim. Biophys. Acta, 1993, 1145(1), 124-133.
Delahunty, M. D.; Rhee, I.; Freed, E. O.; Bonifacino, J. S. Mutational analysis of the fusion peptide of the human immunodeficiency virus type 1: Identification of critical glycine residues. virology, 1996, 218(1), 94-102.
Gordon, L. M.; Mobley, P. W.; Pilpa, R.; Sherman, M. A.; Waring, A. J. Conformational mapping of the N-terminal peptide of HIV-1 gp41 in membrane environments using C-13-enhanced Fourier transform infrared spectroscopy. Biochim. Biophys. Acta-Biomembranes, 2002, 1559(2), 96-120.
Pritsker, M.; Rucker, J.; Hoffman, T. L.; Doms, R. W.; Shai, Y. Effect of nonpolar substitutions of the conserved Phe(11) in the fusion peptide of HIV-1 gp41 on its function, structure, and organization in membranes. Biochemistry, 1999, 38(35), 11359-11371.
Ducarme, P.; Rahman, M.; Brasseur, R. IMPALA: A simple restraint field to simulate the biological membrane in molecular structure studies. Prot. Struct. Funct. Genet., 1998, 30(4), 357-371. (Pubitemid 28117656)
Charloteaux, B.; Lorin, A.; Crowet, J. M.; Stroobant, V.; Lins, L.; Thomas, A.; Brasseur, R. The N-terminal 12 residue long peptide of HIV gp41 is the minimal peptide sufficient to induce significant T-cell-like membrane destabilization in vitro. J. Mol. Biol., 2006, 359(3), 597-609.
Lorin, A.; Lins, L.; Stroobant, V.; Brasseur, R.; Charloteaux, B. The minimal fusion peptide of simian immunodeficiency virus corresponds to the 11 first residues of gp32. J. Pept. Sci., 2008, 14(4), 423-428.
Lorin, A.; Lins, L.; Stroobant, V.; Brasseur, R.; Charloteaux, B. Determination of the minimal fusion peptide of bovine leukemia virus gp30. Biochem. Biophys. Res. Commun., 2007, 355(3), 649-653.
Buchschacher, G. L., Jr.; Freed, E. O.; Panganiban, A. T. Effects of second-site mutations on dominant interference by a human immunodeficiency virus type 1 envelope glycoprotein mutant. J. Virol., 1995, 69(2), 1344-1348.
Thomas, A.; Deshayes, S.; Decaffmeyer, M.; Van Eyck, M. H.; Charloteaux, B.; Brasseur, R. Prediction of peptide structure: how far are we? Prot. Struct. Funct. Genet., 2006, 65(4), 889-897.
Deshayes, S.; Decaffmeyer, M.; Brasseur, R.; Thomas, A. Structural polymorphism of two CPP: An important parameter of activity. Biochim. Biophys. Acta-Biomembranes, 2008, 1778(5), 1197-1205
Gordon, L. M.; Curtain, C. C.; Zhong, Y. C.; Kirkpatrick, A.; Mobley, P. W.; Waring, A. J. The Amino-Terminal Peptide of Hiv-1 Glycoprotein-41 Interacts with Human Erythrocyte-Membranes-Peptide Conformation, Orientation and Aggregation. Biochim. Biophys. Acta, 1992, 1139(4), 257-274.
Jaroniec, C. P.; Kaufman, J. D.; Stahl, S. J.; Viard, M.; Blumenthal, R.; Wingfield, P. T.; Bax, A. Structure and dynamics of micelleassociated human immunodeficiency virus gp41 fusion domain. Biochemisty, 2005, 44(49), 16167-16180.
Pereira, F. B.; Goni, F. M.; Muga, A.; Nieva, J. L. Permeabilization and fusion of uncharged lipid vesicles induced by the HIV-1 fusion peptide adopting an extended conformation: Dose and sequence effects. Biophys. J., 1997, 73(4), 1977-1986.
Rafalski, M.; Lear, J. D.; Degrado, W. F. Phospholipid Interactions of Synthetic Peptides Representing the N-Terminus of Hiv Gp41. Biochemistry, 1990, 29(34), 7917-7922.
Sackett, K.; Shai, Y. The HIV fusion peptide adopts intermolecular parallel beta-sheet structure in membranes when stabilized by the adjacent N-terminal heptad repeat: A C-13 FTIR study. J. Mol. Biol., 2005, 350(4), 790-805.
Yang, J.; Gabrys, C. M.; Weliky, D. P. Solid-state nuclear magnetic resonance evidence for an extended beta strand conformation of the membrane-bound HIV-1 fusion peptide. Biochemistry, 2001, 40(27), 8126-8137.
Yang, R.; Yang, J.; Weliky, D. P. Synthesis, enhanced fusogenicity, and solid state NMR measurements of cross-linked HIV-1 fusion peptides. Biochemistry, 2003, 42(12), 3527-3535.
Yang, R.; Prorok, M.; Castellino, F. J.; Weliky, D. P. A trimeric HIV-1 fusion peptide construct which does not self-associate in aqueous solution and which has 15-fold higher membrane fusion rate. J. Am. Chem. Soc., 2004, 126(45), 14722-14723.
Peisajovich, S. G.; Epand, R. F.; Pritsker, M.; Shai, Y.; Epand, R. M. The polar region consecutive to the HIV fusion peptide participates in membrane fusion. Biochemistry, 2000, 39(7), 1826-1833.
Wexler-Cohen, Y.; Sackett, K.; Shai, Y. The role of the N-terminal heptad repeat of HIV-1 in the actual lipid mixing step as revealed by its substitution with distant coiled coils. Biochemistry, 2005, 44(15), 5853-5861.
Korazim, O.; Sackett, K.; Shai, Y. Functional and structural characterization of HIV-1 gp41 ectodomain regions in phospholipid membranes suggests that the fusion-active conformation is extended. J. Mol. Biol., 2006, 364(5), 1103-1117.
Castano, S.; Desbat, B. Structure and orientation study of fusion peptide FP23 of gp41 from HIV-1 alone or inserted into various lipid membrane models (mono-, bi-and multibi-layers) by FT-IR spectroscopies and Brewster angle microscopy. Biochim. Biophys. Acta-Biomembranes, 2005, 1715(2), 81-95.
Gordon, L. M.; Mobley, P. W.; Lee, W.; Eskandari, S.; Kaznessis, Y. N.; Sherman, M. A.; Waring, A. J. Conformational mapping of the N-terminal peptide of HIV-1 gp41 in lipid detergent and aqueous environments using C-13-enhanced Fourier transform infrared spectroscopy. Prot. Sci., 2004, 13(4), 1012-1030.
Saez-Cirion, A.; Nieva, J. L. Conformational transitions of membrane-bound HIV-1 fusion peptide. Biochim. Biophys. Acta-Biomembranes, 2002, 1564(1), 57-65.
Buzon, V.; Padros, E.; Cladera, J. Interaction of fusion peptides from HIV gp41 with membranes: A time-resolved membrane binding, lipid mixing, and structural study. Biochemistry, 2005, 44(40), 13354-13364.
Li, Y.; Tamm, L. K. Structure and plasticity of the human immunodeficiency virus gp41 fusion domain in lipid micelles and bilayers. Biophys. J., 2007, 93(3), 876-885.
Tamm, L. K.; Lai, A. L.; Li, Y. Combined NMR and EPR spectroscopy to determine structures of viral fusion domains in membranes. Biochim. Biophys. Acta, 2007, 1768(12), 3052-3060.
Weise, K.; Reed, J. Fusion Peptides and Transmembrane Domains of Fusion Proteins are Characterized by Different but Specific Structural Properties. Chembiochem., 2008, 9(6), 934-943
Cohen, F. S.; Melikyan, G. B. The energetics of membrane fusion from binding, through hemifusion, pore formation, and pore enlargement. J. Membrane Biol., 2004, 199(1), 1-14.
Chang, D. K.; Cheng, S. F.; Kantchev, E. A.; Lin, C. H.; Liu, Y. T. Membrane interaction and structure of the transmembrane domain of influenza hemagglutinin and its fusion peptide complex. BMC Biol., 2008, 6, 2.
Wilson, I. A.; Skehel, J. J.; Wiley, D. C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature, 1981, 289(5796), 366-373.
Schroth-Diez, B.; Ludwig, K.; Baljinnyam, B.; Kozerski, C.; Huang, Q.; Herrmann, A. The role of the transmembrane and of the intraviral domain of glycoproteins in membrane fusion of enveloped viruses. Biosci. Rep., 2000, 20(6), 571-595.