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Structural and functional analysis of interhelical interactions in the human immunodeficiency virus type 1 gp41 envelope glycoprotein by alanine-scanning mutagenesis.

Lu M, Stoller MO, Wang S, Liu J, Fagan MB, Nunberg JH
J Virol 75 11146-56 (2001)
Cited: 56 times
EuropePMC logo PMID: 11602754

Abstract

Membrane fusion by human immunodeficiency virus type 1 (HIV-1) is promoted by the refolding of the viral envelope glycoprotein into a fusion-active conformation. The structure of the gp41 ectodomain core in its fusion-active state is a trimer of hairpins in which three antiparallel carboxyl-terminal helices pack into hydrophobic grooves on the surface of an amino-terminal trimeric coiled coil. In an effort to identify amino acid residues in these grooves that are critical for gp41 activation, we have used alanine-scanning mutagenesis to investigate the importance of individual side chains in determining the biophysical properties of the gp41 core and the membrane fusion activity of the gp120-gp41 complex. Alanine substitutions at Leu-556, Leu-565, Val-570, Gly-572, and Arg-579 positions severely impaired membrane fusion activity in envelope glycoproteins that were for the most part normally expressed. Whereas alanine mutations at Leu-565 and Val-570 destabilized the trimer-of-hairpins structure, mutations at Gly-572 and Arg-579 led to the formation of a stable gp41 core. Our results suggest that the Leu-565 and Val-570 residues are important determinants of conserved packing interactions between the amino- and carboxyl-terminal helices of gp41. We propose that the high degree of sequence conservation at Gly-572 and Arg-579 may result from selective pressures imposed by prefusogenic conformations of the HIV-1 envelope glycoprotein. Further analysis of the gp41 activation process may elucidate targets for antiviral intervention.

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  1. HIV-1 envelope glycoprotein structure. Merk A, Subramaniam S. Curr Opin Struct Biol 23 268-276 (2013)
  2. New Biophysical Approaches Reveal the Dynamics and Mechanics of Type I Viral Fusion Machinery and Their Interplay with Membranes. Benhaim MA, Lee KK. Viruses 12 E413 (2020)

Articles - 1i5x mentioned but not cited (4)

  1. Structural and functional analysis of interhelical interactions in the human immunodeficiency virus type 1 gp41 envelope glycoprotein by alanine-scanning mutagenesis. Lu M, Stoller MO, Wang S, Liu J, Fagan MB, Nunberg JH. J Virol 75 11146-11156 (2001)
  2. Bhageerath: an energy based web enabled computer software suite for limiting the search space of tertiary structures of small globular proteins. Jayaram B, Bhushan K, Shenoy SR, Narang P, Bose S, Agrawal P, Sahu D, Pandey V. Nucleic Acids Res 34 6195-6204 (2006)
  3. Computer-Aided Approaches for Targeting HIVgp41. Allen WJ, Rizzo RC. Biology (Basel) 1 311-338 (2012)
  4. Crystal Structure of Refolding Fusion Core of Lassa Virus GP2 and Design of Lassa Virus Fusion Inhibitors. Zhang X, Wang C, Chen B, Wang Q, Xu W, Ye S, Jiang S, Zhu Y, Zhang R. Front Microbiol 10 1829 (2019)


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  2. Common principles and intermediates of viral protein-mediated fusion: the HIV-1 paradigm. Melikyan GB. Retrovirology 5 111 (2008)
  3. The complex antigenicity of a small external region of the C-terminal tail of the HIV-1 gp41 envelope protein: a lesson in epitope analysis. Dimmock NJ. Rev Med Virol 15 365-381 (2005)
  4. Deep Mutational Scanning of Viral Glycoproteins and Their Host Receptors. Narayanan KK, Procko E. Front Mol Biosci 8 636660 (2021)
  5. HIV Infection: Shaping the Complex, Dynamic, and Interconnected Network of the Cytoskeleton. Cabrera-Rodríguez R, Pérez-Yanes S, Lorenzo-Sánchez I, Trujillo-González R, Estévez-Herrera J, García-Luis J, Valenzuela-Fernández A. Int J Mol Sci 24 13104 (2023)

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  1. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. Sanders RW, Vesanen M, Schuelke N, Master A, Schiffner L, Kalyanaraman R, Paluch M, Berkhout B, Maddon PJ, Olson WC, Lu M, Moore JP. J Virol 76 8875-8889 (2002)
  2. HIV-1 envelope proteins complete their folding into six-helix bundles immediately after fusion pore formation. Markosyan RM, Cohen FS, Melikyan GB. Mol Biol Cell 14 926-938 (2003)
  3. Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity. Murakami T, Ablan S, Freed EO, Tanaka Y. J Virol 78 1026-1031 (2004)
  4. Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains. He Y, Cheng J, Lu H, Li J, Hu J, Qi Z, Liu Z, Jiang S, Dai Q. Proc Natl Acad Sci U S A 105 16332-16337 (2008)
  5. A dual-functional paramyxovirus F protein regulatory switch segment: activation and membrane fusion. Russell CJ, Kantor KL, Jardetzky TS, Lamb RA. J Cell Biol 163 363-374 (2003)
  6. Experimental Estimation of the Effects of All Amino-Acid Mutations to HIV's Envelope Protein on Viral Replication in Cell Culture. Haddox HK, Dingens AS, Bloom JD. PLoS Pathog 12 e1006114 (2016)
  7. Identification of a critical motif for the human immunodeficiency virus type 1 (HIV-1) gp41 core structure: implications for designing novel anti-HIV fusion inhibitors. He Y, Cheng J, Li J, Qi Z, Lu H, Dong M, Jiang S, Dai Q. J Virol 82 6349-6358 (2008)
  8. Analysis of the neutralization breadth of the anti-V3 antibody F425-B4e8 and re-assessment of its epitope fine specificity by scanning mutagenesis. Pantophlet R, Aguilar-Sino RO, Wrin T, Cavacini LA, Burton DR. Virology 364 441-453 (2007)
  9. Detailed mechanistic insights into HIV-1 sensitivity to three generations of fusion inhibitors. Eggink D, Langedijk JP, Bonvin AM, Deng Y, Lu M, Berkhout B, Sanders RW. J Biol Chem 284 26941-26950 (2009)
  10. Conserved salt bridge between the N- and C-terminal heptad repeat regions of the human immunodeficiency virus type 1 gp41 core structure is critical for virus entry and inhibition. He Y, Liu S, Li J, Lu H, Qi Z, Liu Z, Debnath AK, Jiang S. J Virol 82 11129-11139 (2008)
  11. Genetic evidence that interhelical packing interactions in the gp41 core are critical for transition of the human immunodeficiency virus type 1 envelope glycoprotein to the fusion-active state. Follis KE, Larson SJ, Lu M, Nunberg JH. J Virol 76 7356-7362 (2002)
  12. Two domains that control prefusion stability and transport competence of the measles virus fusion protein. Doyle J, Prussia A, White LK, Sun A, Liotta DC, Snyder JP, Compans RW, Plemper RK. J Virol 80 1524-1536 (2006)
  13. The M-T hook structure is critical for design of HIV-1 fusion inhibitors. Chong H, Yao X, Sun J, Qiu Z, Zhang M, Waltersperger S, Wang M, Cui S, He Y. J Biol Chem 287 34558-34568 (2012)
  14. Amino acid 36 in the human immunodeficiency virus type 1 gp41 ectodomain controls fusogenic activity: implications for the molecular mechanism of viral escape from a fusion inhibitor. Kinomoto M, Yokoyama M, Sato H, Kojima A, Kurata T, Ikuta K, Sata T, Tokunaga K. J Virol 79 5996-6004 (2005)
  15. Conserved residues in the coiled-coil pocket of human immunodeficiency virus type 1 gp41 are essential for viral replication and interhelical interaction. Mo H, Konstantinidis AK, Stewart KD, Dekhtyar T, Ng T, Swift K, Matayoshi ED, Kati W, Kohlbrenner W, Molla A. Virology 329 319-327 (2004)
  16. Human immunodeficiency virus type 1 variants resistant to first- and second-version fusion inhibitors and cytopathic in ex vivo human lymphoid tissue. Chinnadurai R, Rajan D, Münch J, Kirchhoff F. J Virol 81 6563-6572 (2007)
  17. Protein grafting of an HIV-1-inhibiting epitope. Sia SK, Kim PS. Proc Natl Acad Sci U S A 100 9756-9761 (2003)
  18. Effects of the I559P gp41 change on the conformation and function of the human immunodeficiency virus (HIV-1) membrane envelope glycoprotein trimer. Alsahafi N, Debbeche O, Sodroski J, Finzi A. PLoS One 10 e0122111 (2015)
  19. Role of hydrophobic residues in the central ectodomain of gp41 in maintaining the association between human immunodeficiency virus type 1 envelope glycoprotein subunits gp120 and gp41. York J, Nunberg JH. J Virol 78 4921-4926 (2004)
  20. Discovery of critical residues for viral entry and inhibition through structural Insight of HIV-1 fusion inhibitor CP621-652. Chong H, Yao X, Qiu Z, Qin B, Han R, Waltersperger S, Wang M, Cui S, He Y. J Biol Chem 287 20281-20289 (2012)
  21. Specific enfuvirtide-associated mutational pathways in HIV-1 Gp41 are significantly correlated with an increase in CD4(+) cell count, despite virological failure. Svicher V, Aquaro S, D'Arrigo R, Artese A, Dimonte S, Alcaro S, Santoro MM, Di Perri G, Caputo SL, Bellagamba R, Zaccarelli M, Visco-Comandini U, Antinori A, Narciso P, Ceccherini-Silberstein F, Perno CF. J Infect Dis 197 1408-1418 (2008)
  22. Antiviral activity and conformational features of an octapeptide derived from the membrane-proximal ectodomain of the feline immunodeficiency virus transmembrane glycoprotein. Giannecchini S, Di Fenza A, D'Ursi AM, Matteucci D, Rovero P, Bendinelli M. J Virol 77 3724-3733 (2003)
  23. Design of an engineered N-terminal HIV-1 gp41 trimer with enhanced stability and potency. Dwyer JJ, Wilson KL, Martin K, Seedorff JE, Hasan A, Medinas RJ, Davison DK, Feese MD, Richter HT, Kim H, Matthews TJ, Delmedico MK. Protein Sci 17 633-643 (2008)
  24. Human immunodeficiency virus (HIV) gp41 escape mutants: cross-resistance to peptide inhibitors of HIV fusion and altered receptor activation of gp120. Desmezieres E, Gupta N, Vassell R, He Y, Peden K, Sirota L, Yang Z, Wingfield P, Weiss CD. J Virol 79 4774-4781 (2005)
  25. Role of the simian virus 5 fusion protein N-terminal coiled-coil domain in folding and promotion of membrane fusion. West DS, Sheehan MS, Segeleon PK, Dutch RE. J Virol 79 1543-1551 (2005)
  26. HIV-1 gp41 and gp160 are hyperthermostable proteins in a mesophilic environment. Characterization of gp41 mutants. Krell T, Greco F, Engel O, Dubayle J, Dubayle J, Kennel A, Charloteaux B, Brasseur R, Chevalier M, Sodoyer R, El Habib R. Eur J Biochem 271 1566-1579 (2004)
  27. Identification and characterization of a subpocket on the N-trimer of HIV-1 Gp41: implication for viral entry and drug target. Qiu Z, Chong H, Yao X, Su Y, Cui S, He Y. AIDS 29 1015-1024 (2015)
  28. The six-helix bundle of human immunodeficiency virus Env controls pore formation and enlargement and is initiated at residues proximal to the hairpin turn. Markosyan RM, Leung MY, Cohen FS. J Virol 83 10048-10057 (2009)
  29. Role of envelope processing and gp41 membrane spanning domain in the formation of human immunodeficiency virus type 1 (HIV-1) fusion-competent envelope glycoprotein complex. Welman M, Lemay G, Cohen EA. Virus Res 124 103-112 (2007)
  30. Characterization of HIV-1 envelope gp41 genetic diversity and functional domains following perinatal transmission. Ramakrishnan R, Mehta R, Sundaravaradan V, Davis T, Ahmad N. Retrovirology 3 42 (2006)
  31. HIV-1 gp41 ectodomain enhances Cryptococcus neoformans binding to human brain microvascular endothelial cells via gp41 core-induced membrane activities. Huang SH, Wu CH, Jiang S, Bahner I, Lossinsky AS, Jong AY. Biochem J 438 457-466 (2011)
  32. Evidence for a polytopic form of the E1 envelope glycoprotein of Hepatitis C virus. Migliaccio CT, Follis KE, Matsuura Y, Nunberg JH. Virus Res 105 47-57 (2004)
  33. Hydrophobic mutations in buried polar residues enhance HIV-1 gp41 N-terminal heptad repeat-C-terminal heptad repeat interactions and C-peptides' anti-HIV activity. Zheng B, Wang K, Lu L, Yu F, Cheng M, Jiang S, Liu K, Cai L. AIDS 28 1251-1260 (2014)
  34. Antigenic characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs. Witt KC, Castillo-Menendez L, Ding H, Espy N, Zhang S, Kappes JC, Sodroski J. PLoS One 12 e0170672 (2017)
  35. The application of perfluorooctanoate to investigate trimerization of the human immunodeficiency virus-1 gp41 ectodomain by electrophoresis. Lin CH, Chang CC, Cheng SF, Chang DK. Electrophoresis 29 3175-3182 (2008)
  36. Conserved Residue Asn-145 in the C-Terminal Heptad Repeat Region of HIV-1 gp41 is Critical for Viral Fusion and Regulates the Antiviral Activity of Fusion Inhibitors. Geng X, Liu Z, Yu D, Qin B, Zhu Y, Cui S, Chong H, He Y. Viruses 11 E609 (2019)
  37. The conserved residue Arg46 in the N-terminal heptad repeat domain of HIV-1 gp41 is critical for viral fusion and entry. Wang X, Xiong W, Ma X, Wei M, Chen Y, Lu L, Debnath AK, Jiang S, Pan C. PLoS One 7 e44874 (2012)
  38. Increasing hydrophobicity of residues in an anti-HIV-1 Env peptide synergistically improves potency. Leung MY, Cohen FS. Biophys J 100 1960-1968 (2011)
  39. A novel view of modelling interactions between synthetic and biological polymers via docking. Tsvetkov VB, Serbin AV. J Comput Aided Mol Des 26 1369-1388 (2012)
  40. Efficient trapping of HIV-1 envelope protein by hetero-oligomerization with an N-helix chimera. Ou W, Silver J. Retrovirology 2 51 (2005)
  41. HIV-1 envelope accessible surface and polarity: clade, blood, and brain. Sowmya G, Shamini G, Anita S, Sakharkar M, Mathura V, Rodriguez H, Levine AJ, Singer E, Commins D, Somboonwit C, Sinnott JT, Sidhu HS, Rajaseger G, Pushparaj PN, Kangueane P, Shapshak P. Bioinformation 6 48-56 (2011)
  42. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking: anchors modified polyanions interference with the HIV-1 fusion mediator. Tsvetkov VB, Serbin AV. J Comput Aided Mol Des 28 647-673 (2014)
  43. Six-helix bundle completion in the distal C-terminal heptad repeat region of gp41 is required for efficient human immunodeficiency virus type 1 infection. Liu D, Wang H, Yamamoto M, Song J, Zhang R, Du Q, Kawaguchi Y, Inoue JI, Matsuda Z. Retrovirology 15 27 (2018)
  44. Molecular dynamics studies of the inhibitor C34 binding to the wild-type and mutant HIV-1 gp41: inhibitory and drug resistant mechanism. Ma X, Tan J, Su M, Li C, Zhang X, Wang C. PLoS One 9 e111923 (2014)
  45. Stability of gp41 hairpin and helix bundle assembly probed by combined stacking and circular dichroic approaches. Chang CC, Cheng SF, Lin CH, Chen SS, Chang DK. J Struct Biol 175 406-414 (2011)


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