Skip to main content
PMC home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2005;285:25–66. doi: 10.1007/3-540-26764-6_2

The Many Mechanisms of Viral Membrane Fusion Proteins

L J Earp 11, S E Delos 12, H E Park 11, J M White 12
Editor: Mark Marsh1
PMCID: PMC7122167  PMID: 15609500

Abstract

Every enveloped virus fuses its membrane with a host cell membrane, thereby releasing its genome into the cytoplasm and initiating the viral replication cycle. In each case, one or a small set of viral surface transmembrane glycoproteins mediates fusion. Viral fusion proteins vary in their mode of activation and in structural class. These features combine to yield many different fusion mechanisms. Despite their differences, common principles for how fusion proteins function are emerging: In response to an activating trigger, the metastable fusion protein converts to an extended, in some cases rodlike structure, which inserts into the target membrane via its fusion peptide. A subsequent conformational change causes the fusion protein to fold back upon itself, thereby bringing its fusion peptide and its transmembrane domain—and their attached target and viral membranes—into intimate contact. Fusion ensues as the initial lipid stalk progresses through local hemifusion, and then opening and enlargement of a fusion pore. Here we review recent advances in our understanding of how fusion proteins are activated, how fusion proteins change conformation during fusion, and what is happening to the lipids during fusion. We also briefly discuss the therapeutic potential of fusion inhibitors in treating viral infections.

Keywords: Membrane fusion protein, Class I fusion protein, Class II fusion protein, Influenza HA, HIV Env, Low-pH activation, Receptor activation, Conformational changes, Membrane dynamics, Anti-fusion antivirals

Contributor Information

Mark Marsh, Email: m.marsh@ucl.ac.uk.

J. M. White, Email: jw7g@virginia.edu

References

  1. Abrahamyan L.G., Markosyan R.M., Moore J.P., Cohen F.S., Melikyan G.B. Human immunodeficiency virus type 1 Env with an intersubunit disulfide bond engages coreceptors but requires bond reduction after engagement to induce fusion. J Virol. 2003;77:5829–36. doi: 10.1128/JVI.77.10.5829-5836.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aguilar H.C., Anderson W.F., Cannon P.M. Cytoplasmic tail of moloney murine leukemia virus envelope protein influences the conformation of the extracellular domain: implications for the mechanism of action of the R peptide. J Virol. 2003;77:1281–1291. doi: 10.1128/JVI.77.2.1281-1291.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ahn A., Gibbons D.L., Kielian M. The fusion peptide of Semliki Forest virus associates with sterol-rich membrane domains. J Virol. 2002;76:3267–75. doi: 10.1128/JVI.76.7.3267-3275.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ahn A., Klimjack M.R., Chatterjee P.K., Kielian M. An epitope of the Semliki Forest virus fusion protein exposed during virus-membrane fusion. J Virol. 1999;73:10029–39. doi: 10.1128/jvi.73.12.10029-10039.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Allison S.L., Schalich J., Stiasny K., Mandl C.W., Kunz C., Heinz F.X. Oligomeric rearrangement of tick-borne encephalitis virus envelope proteins induced by an acidic pH. J Virol. 1995;69:695–700. doi: 10.1128/jvi.69.2.695-700.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Allison S.L., Stiasny K., Stadler K., Mandl C.W., Heinz F.X. Mapping of functional elements in the stem-anchor region of tick-borne encephalitis virus envelope protein E. J Virol. 1999;73:5605–12. doi: 10.1128/jvi.73.7.5605-5612.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Allison S.L., Schalich J., Stiasny K., Mandl C.W., Heinz F.X. Mutational evidence for an internal fusion peptide in flavivirus envelope protein E. J Virol. 2001;75:4268–75. doi: 10.1128/JVI.75.9.4268-4275.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Armstrong R.T., Kushnir A.S., White J.M. The transmembrane domain of influenza hemagglutinin exhibits a stringent length requirement to support the hemifusion to fusion transition. J Cell Biol. 2000;151:425–38. doi: 10.1083/jcb.151.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bagai S., Lamb R.A. Quantitative measurement of paramyxovirus fusion: differences in requirements of glycoproteins between simian virus 5 and human parainfluenza virus 3 or Newcastle disease virus. J Virol. 1995;69:6712–9. doi: 10.1128/jvi.69.11.6712-6719.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Baker K.A., Dutch R.E., Lamb R.A., Jardetzky T.S. Structural basis for paramyxovirus-mediated membrane fusion. Mol Cell. 1999;3:309–19. doi: 10.1016/S1097-2765(00)80458-X. [DOI] [PubMed] [Google Scholar]
  11. Barbey-Martin C., Gigant B., Bizebard T., Calder L.J., Wharton S.A., Skehel J.J., Knossow M. An antibody that prevents the hemagglutinin low pH fusogenic transition. Virology. 2002;294:70–4. doi: 10.1006/viro.2001.1320. [DOI] [PubMed] [Google Scholar]
  12. Barbouche R., Miquelis R., Jones I.M., Fenouillet E. Protein-disulfide isomerase-mediated reduction of two disulfide bonds of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is required for fusion. J Biol Chem. 2003;278:3131–3136. doi: 10.1074/jbc.M205467200. [DOI] [PubMed] [Google Scholar]
  13. Barnett A.L., Cunningham J.M. Receptor binding transforms the surface subunit of the mammalian C-type retrovirus envelope protein from an inhibitor to an activator of fusion. J Virol. 2001;75:9096–105. doi: 10.1128/JVI.75.19.9096-9105.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Begona Ruiz-Arguello M., Gonzalez-Reyes L., Calder L.J., Palomo C., Martin D., Saiz M.J., Garcia-Barreno B., Skehel J.J., Melero J.A. Effect of proteolytic processing at two distinct sites on shape and aggregation of an anchorless fusion protein of human respiratory syncytial virus and fate of the intervening segment. Virology. 2002;298:317–26. doi: 10.1006/viro.2002.1497. [DOI] [PubMed] [Google Scholar]
  15. Blumenthal R., Sarkar D.P., Durell S., Howard D.E., Morris S.J. Dilation of the influenza hemagglutinin fusion pore revealed by the kinetics of individual cellcell fusion events. J Cell Biol. 1996;135:63–71. doi: 10.1083/jcb.135.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Bobkova M., Stitz J., Engelstadter M., Cichutek K., Buchholz C.J. Identification of R-peptides in envelope proteins of C-type retroviruses. J Gen Virol. 2002;83:2241–6. doi: 10.1099/0022-1317-83-9-2241. [DOI] [PubMed] [Google Scholar]
  17. Bodian D.L., Yamasaki R.B., Buswell R.L., Stearns J.F., White J.M., Kuntz I.D. Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones. Biochemistry. 1993;32:2967–78. doi: 10.1021/bi00063a007. [DOI] [PubMed] [Google Scholar]
  18. Borrego-Diaz E., Peeples M.E., Markosyan R.M., Melikyan G.B., Cohen F.S. Completion of trimeric hairpin formation of influenza virus hemagglutinin promotes fusion pore opening and enlargement. Virology. 2003;316:234–44. doi: 10.1016/j.virol.2003.07.006. [DOI] [PubMed] [Google Scholar]
  19. Bosch B.J., van der Zee R., de Haan C.A., Rottier P.J. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol. 2003;77:8801–11. doi: 10.1128/JVI.77.16.8801-8811.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Bossart K.N., Wang L.F., Flora M.N., Chua K.B., Lam S.K., Eaton B.T., Broder C.C. Membrane fusion tropism and heterotypic functional activities of the nipah virus and hendra virus envelope glycoproteins. J Virol. 2002;76:11186–11198. doi: 10.1128/JVI.76.22.11186-11198.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Bressanelli S., Stiasny K., Allison S.L., Stura E.A., Duquerroy S., Lescar J., Heinz F.X., Ray F.A. Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J. 2004;23:728–38. doi: 10.1038/sj.emboj.7600064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Bron R., Wahlberg J.M., Garoff H., Wilschut J. Membrane fusion of Semliki Forest virus in a model system: correlation between fusion kinetics and structural changes in the envelope glycoprotein. EMBO J. 1993;12:693–701. doi: 10.1002/j.1460-2075.1993.tb05703.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Brown D.A., London E. Structure and function of sphingolipid-and cholesterol-rich membrane rafts. J Biol Chem. 2000;275:17221–4. doi: 10.1074/jbc.R000005200. [DOI] [PubMed] [Google Scholar]
  24. Bullough P.A., Hughson F.M., Skehel J.J., Wiley D.C. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature. 1994;371:37–43. doi: 10.1038/371037a0. [DOI] [PubMed] [Google Scholar]
  25. Calder L.J., Gonzalez-Reyes L., Garcia-Barreno B., Wharton S.A., Skehel J.J., Wiley D.C., Melero J.A. Electron microscopy of the human respiratory syncytial virus fusion protein and complexes that it forms with monoclonal antibodies. Virology. 2000;271:122–31. doi: 10.1006/viro.2000.0279. [DOI] [PubMed] [Google Scholar]
  26. Carr C.M., Chaudhry C., Kim P.S. Influenza hemagglutinin is spring-loaded by a metastable native conformation. Proc Natl Acad Sci USA. 1997;94:14306–13. doi: 10.1073/pnas.94.26.14306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Carr C.M., Kim P.S. A spring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell. 1993;73:823–32. doi: 10.1016/0092-8674(93)90260-W. [DOI] [PubMed] [Google Scholar]
  28. Cathomen T., Naim H.Y., Cattaneo R. Measles viruses with altered envelope protein cytoplasmic tails gain cell fusion competence. J Virol. 1998;72:1224–34. doi: 10.1128/jvi.72.2.1224-1234.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Chan D.C., Fass D., Berger J.M., Kim P.S. Core structure of gp41 from the HIV envelope glycoprotein. Cell. 1997;89:263–73. doi: 10.1016/S0092-8674(00)80205-6. [DOI] [PubMed] [Google Scholar]
  30. Chan D.C., Kim P.S. HIV entry and its inhibition. Cell. 1998;93:681–4. doi: 10.1016/S0092-8674(00)81430-0. [DOI] [PubMed] [Google Scholar]
  31. Chen J., Lee K.H., Steinhauer D.A., Stevens D.J., Skehel J.J., Wiley D.C. Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell. 1998;95:409–17. doi: 10.1016/S0092-8674(00)81771-7. [DOI] [PubMed] [Google Scholar]
  32. Chen J., Skehel J.J., Wiley D.C. N-and C-terminal residues combine in the fusion-pH influenza hemagglutinin HA(2) subunit to form an N cap that terminates the triple-stranded coiled coil. Proc Natl Acad Sci USA. 1999;96:8967–72. doi: 10.1073/pnas.96.16.8967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Chen L., Gorman J.J., McKimm-Breschkin J., Lawrence L.J., Tulloch P.A., Smith B.J., Colman P.M., Lawrence M.C. The structure of the fusion glycoprotein of Newcastle disease virus suggests a novel paradigm for the molecular mechanism of membrane fusion. Structure. 2001;9:255–66. doi: 10.1016/S0969-2126(01)00581-0. [DOI] [PubMed] [Google Scholar]
  34. Chen S.S., Lee S.F., Wang C.T. Cellular membrane-binding ability of the C-terminal cytoplasmic domain of human immunodeficiency virus type 1 envelope transmembrane protein gp41. J Virol. 2001;75:9925–38. doi: 10.1128/JVI.75.20.9925-9938.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Cianci C., Yu K.L., Dischino D.D., Harte W., Deshpande M., Luo G., Colonno R.J., Meanwell N.A., Krystal M. pH-dependent changes in photoaffinity labeling patterns of the H1 influenza virus hemagglutinin by using an inhibitor of viral fusion. J Virol. 1999;73:1785–94. doi: 10.1128/jvi.73.3.1785-1794.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Cleverley D.Z., Lenard J. The transmembrane domain in viral fusion: essential role for a conserved glycine residue in vesicular stomatitis virus G protein. Proc Natl Acad Sci USA. 1998;95:3425–30. doi: 10.1073/pnas.95.7.3425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Colman P.M., Lawrence M.C. The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol. 2003;4:309–19. doi: 10.1038/nrm1076. [DOI] [PubMed] [Google Scholar]
  38. Corver J., Ortiz A., Allison S.L., Schalich J., Heinz F.X., Wilschut J. Membrane fusion activity of tick-borne encephalitis virus and recombinant subviral particles in a liposomal model system. Virology. 2000;269:37–46. doi: 10.1006/viro.1999.0172. [DOI] [PubMed] [Google Scholar]
  39. Damico R.L., Crane J., Bates P. Receptor-triggered membrane association of a model retroviral glycoprotein. Proc Natl Acad Sci USA. 1998;95:2580–5. doi: 10.1073/pnas.95.5.2580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Danieli T., Pelletier S.L., Henis Y.I., White J.M. Membrane fusion mediated by the influenza virus hemagglutinin requires the concerted action of at least three hemagglutinin trimers. J Cell Biol. 1996;133:559–69. doi: 10.1083/jcb.133.3.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Debnath A.K., Radigan L., Jiang S. Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1. J Med Chem. 1999;42:3203–9. doi: 10.1021/jm990154t. [DOI] [PubMed] [Google Scholar]
  42. Delos S.E., Gilbert J.M., White J.M. The central proline of an internal viral fusion peptide serves two important roles. J Virol. 2000;74:1686–93. doi: 10.1128/JVI.74.4.1686-1693.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Delos S.E., White J.M. Critical role for the cysteines flanking the internal fusion peptide of avian sarcoma/leukosis virus envelope glycoprotein. J Virol. 2000;74:9738–41. doi: 10.1128/JVI.74.20.9738-9741.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Deng R., Wang Z., Mahon P.J., Marinello M., Mirza A., Iorio R.M. Mutations in the Newcastle disease virus hemagglutinin-neuraminidase protein that interfere with its ability to interact with the homologous F protein in the promotion of fusion. Virology. 1999;253:43–54. doi: 10.1006/viro.1998.9501. [DOI] [PubMed] [Google Scholar]
  45. Dennison S.M., Greenfield N., Lenard J., Lentz B.R. VSV transmembrane domain (TMD) peptide promotes PEG-mediated fusion of liposomes in a conformationally sensitive fashion. Biochemistry. 2002;41:14925–14934. doi: 10.1021/bi0203233. [DOI] [PubMed] [Google Scholar]
  46. Di Simone C., Buchmeier M.J. Kinetics and pH dependence of acid-induced structural changes in the lymphocytic choriomeningitis virus glycoprotein complex. Virology. 1995;209:3–9. doi: 10.1006/viro.1995.1225. [DOI] [PubMed] [Google Scholar]
  47. Doms R.W., Helenius A., White J. Membrane fusion activity of the influenza virus hemagglutinin. The low pH-induced conformational change. J Biol Chem. 1985;260:2973–81. [PubMed] [Google Scholar]
  48. Duffus W.A., Levy-Mintz P., Klimjack M.R., Kielian M. Mutations in the putative fusion peptide of Semliki Forest virus affect spike protein oligomerization and virus assembly. J Virol. 1995;69:2471–9. doi: 10.1128/jvi.69.4.2471-2479.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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;14:97–112. doi: 10.3109/09687689709048170. [DOI] [PubMed] [Google Scholar]
  50. Dutch R.E., Lamb R.A. Deletion of the cytoplasmic tail of the fusion protein of the paramyxovirus simian virus 5 affects fusion pore enlargement. J Virol. 2001;75:5363–9. doi: 10.1128/JVI.75.11.5363-5369.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Earp L.J., Delos S.E., Netter R.C., Bates P., White J.M. The avian retrovirus avian sarcoma/leukosis virus subtype A reaches the lipid mixing stage of fusion at neutral pH. J Virol. 2003;77:3058–3066. doi: 10.1128/JVI.77.5.3058-3066.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Eckert D.M., Kim P.S. Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem. 2001;70:777–810. doi: 10.1146/annurev.biochem.70.1.777. [DOI] [PubMed] [Google Scholar]
  53. Eckert D.M., Malashkevich V.N., Hong L.H., Carr P.A., Kim P.S. Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell. 1999;99:103–15. doi: 10.1016/S0092-8674(00)80066-5. [DOI] [PubMed] [Google Scholar]
  54. Edwards T.G., Wyss S., Reeves J.D., Zolla-Pazner S., Hoxie J.A., Doms R.W., Baribaud F. Truncation of the cytoplasmic domain induces exposure of conserved regions in the ectodomain of human immunodeficiency virus type 1 envelope protein. J Virol. 2002;76:2683–91. doi: 10.1128/JVI.76.6.2683-2691.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Einfeld D.A., Hunter E. Expression of the TM protein of Rous sarcoma virus in the absence of SU shows that this domain is capable of oligomerization and intracellular transport. J Virol. 1994;68:2513–20. doi: 10.1128/jvi.68.4.2513-2520.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Fackler O.T., Peterlin B.M. Endocytic entry of HIV-1. Curr Biol. 2000;10:1005–8. doi: 10.1016/S0960-9822(00)00654-0. [DOI] [PubMed] [Google Scholar]
  57. Feng Y., Broder C.C., Kennedy P.E., Berger E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872–7. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  58. Fenouillet E., Barbouche R., Courageot J., Miquelis R. The catalytic activity of protein disulfide isomerase is involved in human immunodeficiency virus envelope-mediated membrane fusion after CD4 cell binding. J Infect Dis. 2001;183:744–52. doi: 10.1086/318823. [DOI] [PubMed] [Google Scholar]
  59. Ferlenghi I., Clarke M., Ruttan T., Allison S.L., Schalich J., Heinz F.X., Harrison S.C., Rey F., Fuller S.D. Molecular organization of a recombinant subviral particle from tick-borne encephalitis virus. Mol Cell. 2001;7:593–602. doi: 10.1016/S1097-2765(01)00206-4. [DOI] [PubMed] [Google Scholar]
  60. Ferrer M., Kapoor T.M., Strassmaier T., Weissenhorn W., Skehel J.J., Oprian D., Schreiber S.L., Wiley D.C., Harrison S.C. Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements. Nat Struct Biol. 1999;6:953–60. doi: 10.1038/13324. [DOI] [PubMed] [Google Scholar]
  61. Fischer C., Schroth-Diez B., Herrmann A., Garten W., Klenk H.D. Acylation of the influenza hemagglutinin modulates fusion activity. Virology. 1998;248:284–94. doi: 10.1006/viro.1998.9286. [DOI] [PubMed] [Google Scholar]
  62. Fredericksen B.L., Whitt M.A. Vesicular stomatitis virus glycoprotein mutations that affect membrane fusion activity and abolish virus infectivity. J Virol. 1995;69:1435–43. doi: 10.1128/jvi.69.3.1435-1443.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Freed E.O., Delwart E.L., Buchschacher G.L.J., Panganiban A.T. A mutation in the human immunodeficiency virus type 1 transmembrane glycoprotein gp41 dominantly interferes with fusion and infectivity. Proc Natl Acad Sci USA. 1992;89:70–4. doi: 10.1073/pnas.89.1.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Freed E.O., Martin M.A. Domains of the human immunodeficiency virus type 1 matrix and gp41 cytoplasmic tail required for envelope incorporation into virions. J Virol. 1996;70:341–51. doi: 10.1128/jvi.70.1.341-351.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Frey S., Marsh M., Gunther S., Pelchen-Matthews A., Stephens P., Ortlepp S., Stegmann T. Temperature dependence of cell-cell fusion induced by the envelope glycoprotein of human immunodeficiency virus type 1. J Virol. 1995;69:1462–72. doi: 10.1128/jvi.69.3.1462-1472.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Fujii G., Horvath S., Woodward S., Eiserling F., Eisenberg D. A molecular model for membrane fusion based on solution studies of an amphiphilic peptide from HIV gp41. Protein Sci. 1992;1:1454–64. doi: 10.1002/pro.5560011107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Furuta R.A., Wild C.T., Weng Y., Weiss C.D. Capture of an early fusion-active conformation of HIV-1 gp41. Nat Struct Biol. 1998;5:276–9. doi: 10.1038/nsb0498-276. [DOI] [PubMed] [Google Scholar]
  68. Gallina A., Hanley T.M., Mandel R., Trahey M., Broder C.C., Viglianti G.A., Ryser H.J. Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry. J Biol Chem. 2002;277:50579–88. doi: 10.1074/jbc.M204547200. [DOI] [PubMed] [Google Scholar]
  69. Gaudin Y., de Kinkelin P., Benmansour A. Mutations in the glycoprotein of viral haemorrhagic septicaemia virus that affect virulence for fish and the pH threshold for membrane fusion. J Gen Virol. 1999;80:1221–9. doi: 10.1099/0022-1317-80-5-1221. [DOI] [PubMed] [Google Scholar]
  70. Gaudin Y., Tuffereau C., Durrer P., Brunner J., Flamand A., Ruigrok R. Rabies virus-induced membrane fusion. Mol Membr Biol. 1999;16:21–31. doi: 10.1080/096876899294724. [DOI] [PubMed] [Google Scholar]
  71. Gawrisch K., Han K.H., Yang J.S., Bergelson L.D., Ferretti J.A. Interaction of peptide fragment 828–848 of the envelope glycoprotein of human immunodeficiency virus type I with lipid bilayers. Biochemistry. 1993;32:3112–8. doi: 10.1021/bi00063a024. [DOI] [PubMed] [Google Scholar]
  72. Gething M.J., Doms R.W., York D., White J. Studies on the mechanism of membrane fusion: site-specific mutagenesis of the hemagglutinin of influenza virus. J Cell Biol. 1986;102:11–23. doi: 10.1083/jcb.102.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Gibbons D.L., Vaney M.C., Roussel A., Vigouroux A., Reilly B., Lepault J., Kielian M., Rey F.A. Conformational change and protein-protein interactions of the fusion protein of Semliki Forest virus. Nature. 2004;427:320–25. doi: 10.1038/nature02239. [DOI] [PubMed] [Google Scholar]
  74. Gilbert J.M., Mason D., White J.M. Fusion of Rous sarcoma virus with host cells does not require exposure to low pH. J Virol. 1990;64:5106–13. doi: 10.1128/jvi.64.10.5106-5113.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Godley L., Pfeifer J., Steinhauer D., Ely B., Shaw G., Kaufmann R., Suchanek E., Pabo C., Skehel J.J., Wiley D.C. Introduction of intersubunit disulfide bonds in the membrane-distal region of the influenza hemagglutinin abolishes membrane fusion activity. Cell. 1992;68:635–45. doi: 10.1016/0092-8674(92)90140-8. [DOI] [PubMed] [Google Scholar]
  76. Golding H., Zaitseva M., de Rosny E., King L.R., Manischewitz J., Sidorov I., Gorny M.K., Zolla-Pazner S., Dimitrov D.S., Weiss C. Dissection of human immunodeficiency virus type 1 entry with neutralizing antibodies to gp41 fusion intermediates. J Virol. 2002;76:6780–90. doi: 10.1128/JVI.76.13.6780-6790.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Gollins S.W., Porterfield J.S. A new mechanism for the neutralization of enveloped viruses by antiviral antibody. Nature. 1986;321:244–6. doi: 10.1038/321244a0. [DOI] [PubMed] [Google Scholar]
  78. Gonzalez-Reyes L., Ruiz-Arguello M.B., Garcia-Barreno B., Calder L., Lopez J.A., Albar J.P., Skehel J.J., Wiley D.C., Melero J.A. Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci USA. 2001;98:9859–64. doi: 10.1073/pnas.151098198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Gruenke J.A., Armstrong R.T., Newcomb W.W., Brown J.C., White J.M. New insights into the spring-loaded conformational change of influenza hemagglutinin. J Virol. 2002;76:4456–66. doi: 10.1128/JVI.76.9.4456-4466.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Gunther-Ausborn S., Schoen P., Bartoldus I., Wilschut J., Stegmann T. Role of hemagglutinin surface density in the initial stages of influenza virus fusion: lack of evidence for cooperativity. J Virol. 2000;74:2714–20. doi: 10.1128/JVI.74.6.2714-2720.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Haffar O.K., Dowbenko D.J., Berman P.W. The cytoplasmic tail of HIV-1 gp160 contains regions that associate with cellular membranes. Virology. 1991;180:439–41. doi: 10.1016/0042-6822(91)90054-F. [DOI] [PubMed] [Google Scholar]
  82. 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;8:715–20. doi: 10.1038/90434. [DOI] [PubMed] [Google Scholar]
  83. He Y., Vassell R., Zaitseva M., Nguyen N., Yang Z., Weng Y., Weiss C. Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites. J Virol. 2003;77:1666–1671. doi: 10.1128/JVI.77.3.1666-1671.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Heinz F.X., Allison S.L. The machinery for flavivirus fusion with host cell membranes. Curr Opin Microbiol. 2001;4:450–5. doi: 10.1016/S1369-5274(00)00234-4. [DOI] [PubMed] [Google Scholar]
  85. Helenius A. Alphavirus and flavivirus glycoproteins: structures and functions. Cell. 1995;81:651–3. doi: 10.1016/0092-8674(95)90523-5. [DOI] [PubMed] [Google Scholar]
  86. Hernandez L.D., Hoffman L.R., Wolfsberg T.G., White J.M. Virus-cell and cellcell fusion. Annu Rev Cell Dev Biol. 1996;12:627–61. doi: 10.1146/annurev.cellbio.12.1.627. [DOI] [PubMed] [Google Scholar]
  87. Hernandez L.D., Peters R.J., Delos S.E., Young J.A., Agard D.A., White J.M. Activation of a retroviral membrane fusion protein: soluble receptor-induced liposome binding of the ALSV envelope glycoprotein. J Cell Biol. 1997;139:1455–64. doi: 10.1083/jcb.139.6.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Hernandez L.D., White J.M. Mutational analysis of the candidate internal fusion peptide of the avian leukosis and sarcoma virus subgroup A envelope glycoprotein. J Virol. 1998;72:3259–67. doi: 10.1128/jvi.72.4.3259-3267.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Hoffman L.R., Kuntz I.D., White J.M. Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: irreversible inhibition of infectivity. J Virol. 1997;71:8808–20. doi: 10.1128/jvi.71.11.8808-8820.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Hunter E. Viral entry and receptors. In: Coffin J. M., editor. Retroviruses. Plainview, NY: Cold Spring Harbor Laboratory Press; 1997. pp. 71–121. [PubMed] [Google Scholar]
  91. Irurzun A., Nieva J.L., Carrasco L. Entry of Semliki forest virus into cells: effects of concanamycin A and nigericin on viral membrane fusion and infection. Virology. 1997;227:488–92. doi: 10.1006/viro.1996.8340. [DOI] [PubMed] [Google Scholar]
  92. Ito H., Watanabe S., Sanchez A., Whitt M.A., Kawaoka Y. Mutational analysis of the putative fusion domain of Ebola virus glycoprotein. J Virol. 1999;73:8907–12. doi: 10.1128/jvi.73.10.8907-8912.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Jahn R., Lang T., Sudhof T.C. Membrane fusion. Cell. 2003;112:519–533. doi: 10.1016/S0092-8674(03)00112-0. [DOI] [PubMed] [Google Scholar]
  94. Januszeski M.M., Cannon P.M., Chen D., Rozenberg Y., Anderson W.F. Functional analysis of the cytoplasmic tail of Moloney murine leukemia virus envelope protein. J Virol. 1997;71:3613–9. doi: 10.1128/jvi.71.5.3613-3619.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Jeffers S.A., Sanders D.A., Sanchez A. Covalent modifications of the ebola virus glycoprotein. J Virol. 2002;76:12463–72. doi: 10.1128/JVI.76.24.12463-12472.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Jiang S., Zhao Q., Debnath A.K. Peptide and non-peptide HIV fusion inhibitors. Curr Pharm Des. 2002;8:563–80. doi: 10.2174/1381612024607180. [DOI] [PubMed] [Google Scholar]
  97. Joshi S.B., Dutch R.E., Lamb R.A. A core trimer of the paramyxovirus fusion protein: parallels to influenza virus hemagglutinin and HIV-1 gp41. Virology. 1998;248:20–34. doi: 10.1006/viro.1998.9242. [DOI] [PubMed] [Google Scholar]
  98. Kamath S., Wong T.C. Membrane structure of the human immunodeficiency virus gp41 fusion domain by molecular dynamics simulation. Biophys J. 2002;83:135–43. doi: 10.1016/S0006-3495(02)75155-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Kanaseki T., Kawasaki K., Murata M., Ikeuchi Y., Ohnishi S. Structural features of membrane fusion between influenza virus and liposome as revealed by quick-freezing electron microscopy. J Cell Biol. 1997;137:1041–56. doi: 10.1083/jcb.137.5.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Kemble G.W., Bodian D.L., Rose J., Wilson I.A., White J.M. Intermonomer disulfide bonds impair the fusion activity of influenza virus hemagglutinin. J Virol. 1992;66:4940–50. doi: 10.1128/jvi.66.8.4940-4950.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Kemble G.W., Danieli T., White J.M. Lipid-anchored influenza hemagglutinin promotes hemifusion, not complete fusion. Cell. 1994;76:383–91. doi: 10.1016/0092-8674(94)90344-1. [DOI] [PubMed] [Google Scholar]
  102. Kielian M. Membrane fusion and the alphavirus life cycle. Adv Virus Res. 1995;45:113–51. doi: 10.1016/s0065-3527(08)60059-7. [DOI] [PubMed] [Google Scholar]
  103. Kielian M., Klimjack M.R., Ghosh S., Duffus W.A. Mechanisms of mutations inhibiting fusion and infection by Semliki Forest virus. J Cell Biol. 1996;134:863–72. doi: 10.1083/jcb.134.4.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Kielian M., Chatterjee P.K., Gibbons D.L., Lu Y.E. Specific roles for lipids in virus fusion and exit. Examples from the alphaviruses. Subcell Biochem. 2000;34:409–55. doi: 10.1007/0-306-46824-7_11. [DOI] [PubMed] [Google Scholar]
  105. Kilby J.M., Hopkins S., Venetta T.M., DiMassimo B., Cloud G.A., Lee J.Y., Alldredge L., Hunter E., Lambert D., Bolognesi D., Matthews T., Johnson M.R., Nowak M.A., Shaw G.M., Saag M.S. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med. 1998;4:1302–7. doi: 10.1038/3293. [DOI] [PubMed] [Google Scholar]
  106. Kim F.J., Manel N., Boublik Y., Battini J.L., Sitbon M. Human T-cell leukemia virus type 1 envelope-mediated syncytium formation can be activated in resistant mammalian cell lines by a carboxy-terminal truncation of the envelope cytoplasmic domain. J Virol. 2003;77:963–969. doi: 10.1128/JVI.77.2.963-969.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Kliger Y., Aharoni A., Rapaport D., Jones P., Blumenthal R., Shai Y. Fusion peptides derived from the HIV type 1 glycoprotein 41 associate within phospholipid membranes and inhibit cell-cell fusion. Structure-function study. J Biol Chem. 1997;272:13496–505. doi: 10.1074/jbc.272.21.13496. [DOI] [PubMed] [Google Scholar]
  108. Kliger Y., Gallo S.A., Peisajovich S.G., Munoz-Barroso I., Avkin S., Blumenthal R., Shai Y. Mode of action of an antiviral peptide from HIV-1. Inhibition at a post-lipid mixing stage. J Biol Chem. 2001;276:1391–7. doi: 10.1074/jbc.M004113200. [DOI] [PubMed] [Google Scholar]
  109. Kliger Y., Shai Y. A leucine zipper-like sequence from the cytoplasmic tail of the HIV-1 envelope glycoprotein binds and perturbs lipid bilayers. Biochemistry. 1997;36:5157–69. doi: 10.1021/bi962935r. [DOI] [PubMed] [Google Scholar]
  110. Korte T., Ludwig K., Booy F.P., Blumenthal R., Herrmann A. Conformational intermediates and fusion activity of influenza virus hemagglutinin. J Virol. 1999;73:4567–74. doi: 10.1128/jvi.73.6.4567-4574.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Kozak S.L., Heard J.M., Kabat D. Segregation of CD4 and CXCR4 into distinct lipid microdomains in T lymphocytes suggests a mechanism for membrane destabilization by human immunodeficiency virus. J Virol. 2002;76:1802–15. doi: 10.1128/JVI.76.4.1802-1815.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Kozerski C., Ponimaskin E., Schroth-Diez B., Schmidt M.F., Herrmann A. Modification of the cytoplasmic domain of influenza virus hemagglutinin affects enlargement of the fusion pore. J Virol. 2000;74:7529–37. doi: 10.1128/JVI.74.16.7529-7537.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Kozlov M.M., Chernomordik L.V. The protein coat in membrane fusion: lessons from fission. Traffic. 2002;3:256–67. doi: 10.1034/j.1600-0854.2002.030403.x. [DOI] [PubMed] [Google Scholar]
  114. Kozlovsky Y., Kozlov M.M. Stalk model of membrane fusion: solution of energy crisis. Biophys J. 2002;82:882–95. doi: 10.1016/S0006-3495(02)75450-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Kuhn R.J., Zhang W., Rossmann M.G., Pletnev S.V., Corver J., Lenches E., Jones C.T., Mukhopadhyay S., Chipman P.R., Strauss E.G., Baker T.S., Strauss J.H. Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell. 2002;108:717–25. doi: 10.1016/S0092-8674(02)00660-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Kwong P.D., Wyatt R., Robinson J., Sweet R.W., Sodroski J., Hendrickson W. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998;393:648–59. doi: 10.1038/31405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Lamb R.A. Paramyxovirus fusion: a hypothesis for changes. Virology. 1993;197:1–11. doi: 10.1006/viro.1993.1561. [DOI] [PubMed] [Google Scholar]
  118. Lambert D.M., Barney S., Lambert A.L., Guthrie K., Medinas R., Davis D.E., Bucy T., Erickson J., Merutka G., Petteway S.R.J. Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. Proc Natl Acad Sci USA. 1996;93:2186–91. doi: 10.1073/pnas.93.5.2186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Lavillette D., Boson B., Russell S.J., Cosset F.L. Activation of membrane fusion by murine leukemia viruses is controlled in cis or in trans by interactions between the receptor-binding domain and a conserved disulfide loop of the carboxy terminus of the surface glycoprotein. J Virol. 2001;75:3685–95. doi: 10.1128/JVI.75.8.3685-3695.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Lavillette D., Maurice M., Roche C., Russell S.J., Sitbon M., Cosset F.L. A proline-rich motif downstream of the receptor binding domain modulates conformation and fusogenicity of murine retroviral envelopes. J Virol. 1998;72:9955–65. doi: 10.1128/jvi.72.12.9955-9965.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Lescar J., Roussel A., Wien M.W., Navaza J., Fuller S.D., Wengler G., Rey F.A. The fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH. Cell. 2001;105:137–48. doi: 10.1016/S0092-8674(01)00303-8. [DOI] [PubMed] [Google Scholar]
  122. Li M., Yang C., Compans R.W. Mutations in the cytoplasmic tail of murine leukemia virus envelope protein suppress fusion inhibition by R peptide. J Virol. 2001;75:2337–44. doi: 10.1128/JVI.75.5.2337-2344.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Li Y., Drone C., Sat E., Ghosh H.P. Mutation analysis of the vesicular stomatitis virus glycoprotein G for membrane fusion domains. J Virol. 1993;67:4070–7. doi: 10.1128/jvi.67.7.4070-4077.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Li Y., Han X., Tamm L.K. Thermodynamics of fusion peptide-membrane interactions. Biochemistry. 2003;42:7245–51. doi: 10.1021/bi0341760. [DOI] [PubMed] [Google Scholar]
  125. Lu M., Blacklow S.C., Kim P.S. A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol. 1995;2:1075–82. doi: 10.1038/nsb1295-1075. [DOI] [PubMed] [Google Scholar]
  126. Luciw P.A., Shaw K.E., Shacklett B.L., Marthas M.L. Importance of the intracytoplasmic domain of the simian immunodeficiency virus (SIV) envelope glycoprotein for pathogenesis. Virology. 1998;252:9–16. doi: 10.1006/viro.1998.9467. [DOI] [PubMed] [Google Scholar]
  127. Markosyan R.M., Cohen F.S., Melikyan G.B. HIV-1 envelope proteins complete their folding into six-helix bundles immediately after fusion pore formation. Mol Biol Cell. 2003;14:926–38. doi: 10.1091/mbc.E02-09-0573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Markovic I., Leikina E., Zhukovsky M., Zimmerberg J., Chernomordik L.V. Synchronized activation and refolding of influenza hemagglutinin in multimeric fusion machines. J Cell Biol. 2001;155:833–44. doi: 10.1083/jcb.200103005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Markovic I., Pulyaeva H., Sokoloff A., Chernomordik L.V. Membrane fusion mediated by baculovirus gp64 involves assembly of stable gp64 trimers into multiprotein aggregates. J Cell Biol. 1998;143:1155–66. doi: 10.1083/jcb.143.5.1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Martin I., Ruysschaert J.M. Common properties of fusion peptides from diverse systems. Biosci Rep. 2000;20:483–500. doi: 10.1023/A:1010454803579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Martin I.I., Ruysschaert J., Epand R.M. Role of the N-terminal peptides of viral envelope proteins in membrane fusion. Adv Drug Deliv Rev. 1999;38:233–255. doi: 10.1016/S0169-409X(99)00031-9. [DOI] [PubMed] [Google Scholar]
  132. Matsuyama S, Delos SE, and White JM (2004) Sequential roles of receptor binding and low pH in forming prehairpin and hairpin conformations of an avian retroviral envelope glycoprotein. J Virol (in press) [DOI] [PMC free article] [PubMed]
  133. McClure M.O., Sommerfelt M.A., Marsh M., Weiss R.A. The pH independence of mammalian retrovirus infection. J Gen Virol. 1990;71:767–73. doi: 10.1099/0022-1317-71-4-767. [DOI] [PubMed] [Google Scholar]
  134. McGinnes L.W., Gravel K., Morrison T.G. Newcastle disease virus HN protein alters the conformation of the F protein at cell surfaces. J Virol. 2002;76:12622–33. doi: 10.1128/JVI.76.24.12622-12633.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Melikyan G.B., Brener S.A., Ok D.C., Cohen F.S. Inner but not outer membrane leaflets control the transition from glycosylphosphatidylinositol-anchored influenza hemagglutinin-induced hemifusion to full fusion. J Cell Biol. 1997;136:995–1005. doi: 10.1083/jcb.136.5.995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Melikyan G.B., Jin H., Lamb R.A., Cohen F.S. The role of the cytoplasmic tail region of influenza virus hemagglutinin in formation and growth of fusion pores. Virology. 1997;235:118–28. doi: 10.1006/viro.1997.8686. [DOI] [PubMed] [Google Scholar]
  137. Melikyan G.B., Markosyan R.M., Hemmati H., Delmedico M.K., Lambert D.M., Cohen F.S. Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. J Cell Biol. 2000;151:413–23. doi: 10.1083/jcb.151.2.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  138. Melikyan G.B., Markosyan R.M., Roth M.G., Cohen F.S. A point mutation in the transmembrane domain of the hemagglutinin of influenza virus stabilizes a hemifusion intermediate that can transit to fusion. Mol Biol Cell. 2000;11:3765–75. doi: 10.1091/mbc.11.11.3765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Modis Y., Ogata S., Clements D., Harrison S.C. Structure of the dengue virus envelope protein after membrane fusion. Nature. 2004;427:313–9. doi: 10.1038/nature02165. [DOI] [PubMed] [Google Scholar]
  140. Mothes W., Boerger A.L., Narayan S., Cunningham J.M., Young J.A. Retroviral entry mediated by receptor priming and low pH triggering of an envelope glycoprotein. Cell. 2000;103:679–89. doi: 10.1016/S0092-8674(00)00170-7. [DOI] [PubMed] [Google Scholar]
  141. Munoz-Barroso I., Durell S., Sakaguchi K., Appella E., Blumenthal R. Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41. J Cell Biol. 1998;140:315–23. doi: 10.1083/jcb.140.2.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Munoz-Barroso I., Salzwedel K., Hunter E., Blumenthal R. Role of the membrane-proximal domain in the initial stages of human immunodeficiency virus type 1 envelope glycoprotein-mediated membrane fusion. J Virol. 1999;73:6089–92. doi: 10.1128/jvi.73.7.6089-6092.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Netter RC (2002) Ph.D Dissertation. University of Pennsylvania.
  144. Nir S., Duzgunes N., de Lima M.C., Hoekstra D. Fusion of enveloped viruses with cells and liposomes. Activity and inactivation. Cell Biophys. 1990;17:181–201. doi: 10.1007/BF02990496. [DOI] [PubMed] [Google Scholar]
  145. Nussbaum O., Broder C.C., Berger E.A. Fusogenic mechanisms of enveloped-virus glycoproteins analyzed by a novel recombinant vaccinia virus-based assay quantitating cell fusion-dependent reporter gene activation. J Virol. 1994;68:5411–22. doi: 10.1128/jvi.68.9.5411-5422.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  146. Ohuchi M., Ohuchi R., Sakai T., Matsumoto A. Tight binding of influenza virus hemagglutinin to its receptor interferes with fusion pore dilation. J Virol. 2002;76:1405–13. doi: 10.1128/JVI.76.24.12405-12413.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Owens R.J., Burke C., Rose J.K. Mutations in the membrane-spanning domain of the human immunodeficiency virus envelope glycoprotein that affect fusion activity. J Virol. 1994;68:570–4. doi: 10.1128/jvi.68.1.570-574.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Park H.E., Gruenke J.A., White J.M. Leash in the groove mechanism of membrane fusion. Nat Struct Biol. 2003;10:1048–53. doi: 10.1038/nsb1012. [DOI] [PubMed] [Google Scholar]
  149. Paterson R.G., Russell C.J., Lamb R.A. Fusion protein of the paramyxovirus SV5: destabilizing and stabilizing mutants of fusion activation. Virology. 2000;270:17–30. doi: 10.1006/viro.2000.0267. [DOI] [PubMed] [Google Scholar]
  150. Pelkmans L., Helenius A. Insider information: what viruses tell us about endocytosis. Curr Opin Cell Biol. 2003;15:414–22. doi: 10.1016/S0955-0674(03)00081-4. [DOI] [PubMed] [Google Scholar]
  151. Percherancier Y., Lagane B., Planchenault T., Staropoli I., Altmeyer R., Virelizier J.L., Arenzana-Seisdedos F., Hoessli D.C., Bachelerie F. HIV-1 entry into T-cells is not dependent on CD4 and CCR5 localization to sphingolipid-enriched, detergent-resistant, raft membrane domains. J Biol Chem. 2003;278:3153–3161. doi: 10.1074/jbc.M207371200. [DOI] [PubMed] [Google Scholar]
  152. Pereira F.B., Goni F.M., Nieva J.L. Liposome destabilization induced by the HIV-1 fusion peptide effect of a single amino acid substitution. FEBS Lett. 1995;362:243–6. doi: 10.1016/0014-5793(95)00257-A. [DOI] [PubMed] [Google Scholar]
  153. Pietschmann T., Zentgraf H., Rethwilm A., Lindemann D. An evolutionarily conserved positively charged amino acid in the putative membrane-spanning domain of the foamy virus envelope protein controls fusion activity. J Virol. 2000;74:4474–82. doi: 10.1128/JVI.74.10.4474-4482.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Piller S.C., Dubay J.W., Derdeyn C.A., Hunter E. Mutational analysis of conserved domains within the cytoplasmic tail of gp41 from human immunodeficiency virus type 1: effects on glycoprotein incorporation and infectivity. J Virol. 2000;74:11717–23. doi: 10.1128/JVI.74.24.11717-11723.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Pinter A., Kopelman R., Li Z., Kayman S.C., Sanders D.A. Localization of the labile disulfide bond between SU and TM of the murine leukemia virus envelope protein complex to a highly conserved CWLC motif in SU that resembles the active-site sequence of thiol-disulfide exchange enzymes. J Virol. 1997;71:8073–7. doi: 10.1128/jvi.71.10.8073-8077.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  156. Popik W., Alce T.M., Au W.C. Human immunodeficiency virus type 1 uses lipid raft-colocalized CD4 and chemokine receptors for productive entry into CD4(+) T cells. J Virol. 2002;76:4709–22. doi: 10.1128/JVI.76.10.4709-4722.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  157. Puri A., Winick J., Lowy R.J., Covell D., Eidelman O., Walter A., Blumenthal R. Activation of vesicular stomatitis virus fusion with cells by pretreatment at low pH. J Biol Chem. 1988;263:4749–53. [PubMed] [Google Scholar]
  158. Qiao H., Armstrong R.T., Melikyan G.B., Cohen F.S., White J.M. A specific point mutant at position 1 of the influenza hemagglutinin fusion peptide displays a hemifusion phenotype. Mol Biol Cell. 1999;10:2759–69. doi: 10.1091/mbc.10.8.2759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  159. Qiao H., Pelletier S.L., Hoffman L., Hacker J., Armstrong R.T., White J.M. Specific single or double proline substitutions in the “spring-loaded” coiled-coil region of the influenza hemagglutinin impair or abolish membrane fusion activity. J Cell Biol. 1998;141:1335–47. doi: 10.1083/jcb.141.6.1335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  160. Ragheb J.A., Anderson W.F. pH-independent murine leukemia virus ecotropic envelope-mediated cell fusion: implications for the role of the R peptide and p12E TM in viral entry. J Virol. 1994;68:3220–31. doi: 10.1128/jvi.68.5.3220-3231.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  161. Reeves J.D., Gallo S.A., Ahmad N., Miamidian J.L., Harvey P.E., Sharron M., Pohlman S., Sfakianos J.N., Derdeyn C.A., Blumenthal R., Hunter E., Doms R.W. Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA. 2002;99:16249–54. doi: 10.1073/pnas.252469399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  162. Rein A., Mirro J., Haynes J.G., Ernst S.M., Nagashima K. Function of the cytoplasmic domain of a retroviral transmembrane protein: p15E-p2E cleavage activates the membrane fusion capability of the murine leukemia virus Env protein. J Virol. 1994;68:1773–81. doi: 10.1128/jvi.68.3.1773-1781.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  163. Rey F.A., Heinz F.X., Mandl C., Kunz C., Harrison S.C. The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution. Nature. 1995;375:291–8. doi: 10.1038/375291a0. [DOI] [PubMed] [Google Scholar]
  164. Rousso I., Mixon M.B., Chen B.K., Kim P.S. Palmitoylation of the HIV-1 envelope glycoprotein is critical for viral infectivity. Proc Natl Acad Sci USA. 2000;97:13523–5. doi: 10.1073/pnas.240459697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  165. Russell C.J., Jardetzky T.S., Lamb R.A. Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion. EMBO J. 2001;20:4024–34. doi: 10.1093/emboj/20.15.4024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  166. Saez-Cirion A., Gomara M.J., Agirre A., Nieva J.L. Pre-transmembrane sequence of Ebola glycoprotein. Interfacial hydrophobicity distribution and interaction with membranes. FEBS Lett. 2003;533:47–53. doi: 10.1016/S0014-5793(02)03747-X. [DOI] [PubMed] [Google Scholar]
  167. Saez-Cirion A., Nir S., Lorizate M., Agirre A., Cruz A., Perez-Gil J., Nieva J.L. Sphingomyelin and cholesterol promote HIV-1 gp41 pretransmembrane sequence surface aggregation and membrane restructuring. J Biol Chem. 2002;277:21776–85. doi: 10.1074/jbc.M202255200. [DOI] [PubMed] [Google Scholar]
  168. Sakai T., Ohuchi R., Ohuchi M. Fatty acids on the A/USSR/77 influenza virus hemagglutinin facilitate the transition from hemifusion to fusion pore formation. J Virol. 2002;76:4603–11. doi: 10.1128/JVI.76.9.4603-4611.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  169. Salzwedel K., West J.T., Hunter E. A conserved tryptophan-rich motif in the membrane-proximal region of the human immunodeficiency virus type 1 gp41 ectodomain is important for Env-mediated fusion and virus infectivity. J Virol. 1999;73:2469–80. doi: 10.1128/jvi.73.3.2469-2480.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  170. Schibli D.J., Montelaro R.C., Vogel H.J. The membrane-proximal tryptophan-rich region of the HIV glycoprotein, gp41, forms a well-defined helix in dodecylphosphocholine micelles. Biochemistry. 2001;40:9570–8. doi: 10.1021/bi010640u. [DOI] [PubMed] [Google Scholar]
  171. Schmid E., Zurbriggen A., Gassen U., Rima B., ter Meulen V., Schneider-Schaulies J. Antibodies to CD9, a tetraspan transmembrane protein, inhibit canine distemper virus-induced cell-cell fusion but not virus-cell fusion. J Virol. 2000;74:7554–61. doi: 10.1128/JVI.74.16.7554-7561.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  172. Schoch C., Blumenthal R. Role of the fusion peptide sequence in initial stages of influenza hemagglutinin-induced cell fusion. J Biol Chem. 1993;268:9267–74. [PubMed] [Google Scholar]
  173. Schultz A., Rein A. Maturation of murine leukemia virus Env proteins in the absence of other viral proteins. Virology. 1985;145:335–9. doi: 10.1016/0042-6822(85)90168-0. [DOI] [PubMed] [Google Scholar]
  174. Seth S., Vincent A., Compans R.W. Mutations in the cytoplasmic domain of a paramyxovirus fusion glycoprotein rescue syncytium formation and eliminate the hemagglutinin-neuraminidase protein requirement for membrane fusion. J Virol. 2003;77:167–78. doi: 10.1128/JVI.77.1.167-178.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  175. Shin J.S., Abraham S.N. Caveolae as portals of entry for microbes. Microbes Infect. 2001;3:755–61. doi: 10.1016/S1286-4579(01)01423-X. [DOI] [PubMed] [Google Scholar]
  176. Sjoberg M., Garoff H. Interactions between the transmembrane segments of the alphavirus E1 and E2 proteins play a role in virus budding and fusion. J Virol. 2003;77:3441–3450. doi: 10.1128/JVI.77.6.3441-3450.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  177. Skehel J.J., Cross K., Steinhauer D., Wiley D.C. Influenza fusion peptides. Biochem Soc Trans. 2001;29:623–6. doi: 10.1042/BST0290623. [DOI] [PubMed] [Google Scholar]
  178. Skehel J.J., Wiley D.C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem. 2000;69:531–69. doi: 10.1146/annurev.biochem.69.1.531. [DOI] [PubMed] [Google Scholar]
  179. Staschke K.A., Hatch S.D., Tang J.C., Hornback W.J., Munroe J.E., Colacino J.M., Muesing M.A. Inhibition of influenza virus hemagglutinin-mediated membrane fusion by a compound related to podocarpic acid. Virology. 1998;248:264–274. doi: 10.1006/viro.1998.9273. [DOI] [PubMed] [Google Scholar]
  180. Stegmann T., Bartoldus I., Zumbrunn J. Influenza hemagglutinin-mediated membrane fusion: influence of receptor binding on the lag phase preceding fusion. Biochemistry. 1995;34:1825–32. doi: 10.1021/bi00006a002. [DOI] [PubMed] [Google Scholar]
  181. Stegmann T., Booy F.P., Wilschut J. Effects of low pH on influenza virus. Activation and inactivation of the membrane fusion capacity of the hemagglutinin. J Biol Chem. 1987;262:17744–9. [PubMed] [Google Scholar]
  182. Stein B.S., Gowda S.D., Lifson J.D., Penhallow R.C., Bensch K.G., Engleman E.G. pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to the plasma membrane. Cell. 1987;49:659–68. doi: 10.1016/0092-8674(87)90542-3. [DOI] [PubMed] [Google Scholar]
  183. Stiasny K., Allison S.L., Mandl C.W., Heinz F.X. Role of metastability and acidic pH in membrane fusion by tick-borne encephalitis virus. J Virol. 2001;75:7392–7398. doi: 10.1128/JVI.75.16.7392-7398.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  184. Stiasny K., Allison S.L., Marchler-Bauer A., Kunz C., Heinz F.X. Structural requirements for low-pH-induced rearrangements in the envelope glycoprotein of tick-borne encephalitis virus. J Virol. 1996;70:8142–8147. doi: 10.1128/jvi.70.11.8142-8147.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  185. Stiasny K., Allison S.L., Schalich J., Heinz F.X. Membrane interactions of the tick-borne encephalitis virus fusion protein E at low pH. J Virol. 2002;76:3784–90. doi: 10.1128/JVI.76.8.3784-3790.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  186. Stone-Hulslander J., Morrison T.G. Detection of an interaction between the HN and F proteins in Newcastle disease virus-infected cells. J Virol. 1997;71:6287–95. doi: 10.1128/jvi.71.9.6287-6295.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  187. Suarez T., Gallaher W.R., Agirre A., Goni F.M., Nieva J.L. Membrane interface-interacting sequences within the ectodomain of the human immunodeficiency virus type 1 envelope glycoprotein: putative role during viral fusion. J Virol. 2000;74:8038–47. doi: 10.1128/JVI.74.17.8038-8047.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  188. Suomalainen M. Lipid rafts and assembly of enveloped viruses. Traffic. 2002;3:705–9. doi: 10.1034/j.1600-0854.2002.31002.x. [DOI] [PubMed] [Google Scholar]
  189. Taguchi F., Matsuyama S. Soluble receptor potentiates receptor-independent infection by murine coronavirus. J Virol. 2002;76:950–8. doi: 10.1128/JVI.76.3.950-958.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  190. Takimoto T., Taylor G.L., Connaris H.C., Crennell S.J., Portner A. Role of the hemagglutinin-neuraminidase protein in the mechanism of paramyxovirus-cell membrane fusion. J Virol. 2002;76:13028–33. doi: 10.1128/JVI.76.24.13028-13033.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  191. Tamm L.K., Han X. Viral fusion peptides: a tool set to disrupt and connect biological membranes. Biosci Rep. 2000;20:501–18. doi: 10.1023/A:1010406920417. [DOI] [PubMed] [Google Scholar]
  192. Tamm L.K., Han X., Li Y., Lai A.L. Structure and function of membrane fusion peptides. Biopolymers. 2002;66:249–60. doi: 10.1002/bip.10261. [DOI] [PubMed] [Google Scholar]
  193. Taylor G.M., Sanders D.A. The role of the membrane-spanning domain sequence in glycoprotein-mediated membrane fusion. Mol Biol Cell. 1999;10:2803–15. doi: 10.1091/mbc.10.9.2803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  194. Tong S., Compans R.W. Oligomerization, secretion, and biological function of an anchor-free parainfluenza virus type 2 (PI2) fusion protein. Virology. 2000;270:368–76. doi: 10.1006/viro.2000.0286. [DOI] [PubMed] [Google Scholar]
  195. Tong S., Li M., Vincent A., Compans R.W., Fritsch E., Beier R., Klenk C., Ohuchi M., Klenk H.D. Regulation of fusion activity by the cytoplasmic domain of a paramyxovirus F protein. Virology. 2002;301:322–333. doi: 10.1006/viro.2002.1594. [DOI] [PubMed] [Google Scholar]
  196. Vashishtha M., Phalen T., Marquardt M.T., Ryu J.S., Ng A.C., Kielian M. A single point mutation controls the cholesterol dependence of Semliki Forest virus entry and exit. J Cell Biol. 1998;140:91–9. doi: 10.1083/jcb.140.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  197. Viard M., Parolini I., Sargiacomo M., Fecchi K., Ramoni C., Ablan S., Ruscetti F.W., Wang J.M., Blumenthal R. Role of cholesterol in human immunodeficiency virus type 1 envelope protein-mediated fusion with host cells. J Virol. 2002;76:11584–95. doi: 10.1128/JVI.76.22.11584-11595.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  198. Waarts B.L., Bittman R., Wilschut J. Sphingolipid and cholesterol dependence of alphavirus membrane fusion. Lack of correlation with lipid raft formation in target liposomes. J Biol Chem. 2002;277:38141–38147. doi: 10.1074/jbc.M206998200. [DOI] [PubMed] [Google Scholar]
  199. Wahlberg J.M., Bron R., Wilschut J., Garoff H. Membrane fusion of Semliki Forest virus involves homotrimers of the fusion protein. J Virol. 1992;66:7309–18. doi: 10.1128/jvi.66.12.7309-7318.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  200. Wahlberg J.M., Garoff H. Membrane fusion process of Semliki Forest virus. I: Low pH-induced rearrangement in spike protein quaternary structure precedes virus penetration into cells. J Cell Biol. 1992;116:339–48. doi: 10.1083/jcb.116.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  201. Weber T., Paesold G., Galli C., Mischler R., Semenza G., Brunner J. Evidence for H+-induced insertion of influenza hemagglutinin HA2 N-terminal segment into viral membrane. J Biol Chem. 1994;269:18353–8. [PubMed] [Google Scholar]
  202. Weissenhorn W., Carfi A., Lee K.H., Skehel J.J., Wiley D.C. Crystal structure of the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain. Mol Cell. 1998;2:605–16. doi: 10.1016/S1097-2765(00)80159-8. [DOI] [PubMed] [Google Scholar]
  203. Weissenhorn W., Dessen A., Calder L.J., Harrison S.C., Skehel J.J., Wiley D.C. Structural basis for membrane fusion by enveloped viruses. Mol Membr Biol. 1999;16:3–9. doi: 10.1080/096876899294706. [DOI] [PubMed] [Google Scholar]
  204. Weissenhorn W., Dessen A., Harrison S.C., Skehel J.J., Wiley D.C. Atomic structure of the ectodomain from HIV-1 gp41. Nature. 1997;387:426–30. doi: 10.1038/387426a0. [DOI] [PubMed] [Google Scholar]
  205. West J.T., Johnston P.B., Dubay S.R., Hunter E. Mutations within the putative membrane-spanning domain of the simian immunodeficiency virus transmembrane glycoprotein define the minimal requirements for fusion, incorporation, and infectivity. J Virol. 2001;75:9601–12. doi: 10.1128/JVI.75.20.9601-9612.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  206. Wharton S.A., Skehel J.J., Wiley D.C. Temperature dependence of fusion by sendai virus. Virology. 2000;271:71–78. doi: 10.1006/viro.2000.0280. [DOI] [PubMed] [Google Scholar]
  207. White J., Helenius A. pH-dependent fusion between the Semliki Forest virus membrane and liposomes. Proc Natl Acad Sci USA. 1980;77:3273–7. doi: 10.1073/pnas.77.6.3273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  208. White J., Kartenbeck J., Helenius A. Fusion of Semliki forest virus with the plasma membrane can be induced by low pH. J Cell Biol. 1980;87:264–72. doi: 10.1083/jcb.87.1.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  209. White J., Kartenbeck J., Helenius A. Membrane fusion activity of influenza virus. EMBO J. 1982;1:217–22. doi: 10.1002/j.1460-2075.1982.tb01150.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  210. White J.M. Viral and cellular membrane fusion proteins. Annu Rev Physiol. 1990;52:675–97. doi: 10.1146/annurev.ph.52.030190.003331. [DOI] [PubMed] [Google Scholar]
  211. Wilson I.A., Skehel J.J., Wiley D.C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution. Nature. 1981;289:366–373. doi: 10.1038/289366a0. [DOI] [PubMed] [Google Scholar]
  212. Xiang S.H., Kwong P.D., Gupta R., Rizzuto C.D., Casper D.J., Wyatt R., Wang L., Hendrickson W.A., Doyle M.L., Sodroski J. Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein. J Virol. 2002;76:9888–9899. doi: 10.1128/JVI.76.19.9888-9899.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  213. Yang C., Compans R.W. Analysis of the cell fusion activities of chimeric simian immunodeficiency virus-murine leukemia virus envelope proteins: inhibitory effects of the R peptide. J Virol. 1996;70:248–54. doi: 10.1128/jvi.70.1.248-254.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  214. Yang L., Huang H.W. Observation of a membrane fusion intermediate structure. Science. 2002;297:1877–9. doi: 10.1126/science.1074354. [DOI] [PubMed] [Google Scholar]
  215. Yao Q., Hu X., Compans R.W. Association of the parainfluenza virus fusion and hemagglutinin-neuraminidase glycoproteins on cell surfaces. J Virol. 1997;71:650–6. doi: 10.1128/jvi.71.1.650-656.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  216. Young J.K., Li D., Abramowitz M.C., Morrison T.G. Interaction of peptides with sequences from the Newcastle disease virus fusion protein heptad repeat regions. J Virol. 1999;73:5945–56. doi: 10.1128/jvi.73.7.5945-5956.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  217. Zarkik S., Defrise-Quertain F., Portetelle D., Burny A., Ruysschaert J.M. Fusion of bovine leukemia virus with target cells monitored by R18 fluorescence and PCR assays. J Virol. 1997;71:738–40. doi: 10.1128/jvi.71.1.738-740.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  218. Zhou J., Dutch R.E., Lamb R.A. Proper spacing between heptad repeat B and the transmembrane domain boundary of the paramyxovirus SV5 F protein is critical for biological activity. Virology. 1997;239:327–39. doi: 10.1006/viro.1997.8917. [DOI] [PubMed] [Google Scholar]

Articles from Membrane Trafficking in Viral Replication are provided here courtesy of Nature Publishing Group

RESOURCES