ENV - Envelope polyprotein

HIV ENV is a polyprotein precursor (gp160), which is processed by cellular proteases to give a non-covalent complex of an external glycoprotein (SU / gp120) and a transmembrane glycoprotein (TM / gp41).



PDB-1GC1: Envelope protein complex with gp120 (pink ribbon), CD4 (yellow ribbon), Antibody 17B light chain (blue ribbon) and Antibody 17B heavy chain (green ribbon)  - produced using SwissModel/SPDBV/POVray

Key web links:
ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB: 1GC1 (HIV-1 ENV)
UniProt: P04578 (HIV-1 HXB2 ENV)
Chime Tutorial: not available
HIV-1/Human Protein Interaction DB: HIV-1 Env
Los Alamos HIV structure DB: HIV ENV
EMBL: K03455 [EMBL/GenBank/DDBJ]


Function:

  • Mediates virion attachment and entry into the host cell by binding to the CD4 attachment receptor.
  • This ENV-CD4 interaction induces a structural rearrangement of the ENV protein, which creates a high affinity binding site for attachment to chemokine entry receptors like CXCR4 and/or CCR5.
  • Polyprotein precursor for glycoproteins that occur on the surface of virions.
  • Forms complexes with CD4 receptors within the Endoplasmic Reticulum which decreases CD4 presence on the cell surface.

Localization:

  • Cell plasma membrane
  • Virion envelope
  • Host cytoplasm

Additional Information:

  • Late timing of expression.
  • Translated from singly spliced mRNA.
  • Synthesised in the Endoplasmic Reticulum.
  • Migrates through the Golgi complex.
  • Undergoes glycosylation within Golgi complex.
  • Glycosylation consists of 25 to 30 complex N-linked carbohydrate side chains on Asparagine residues.
  • Glycosylation is required for infectivity .
  • CCR5-using HIV-1 strains predominate in the early stages of disease .
  • CXCR4-using HIV strains are associated with an increase in disease progression .


Env Function & Host-Virus Protein Interactions:[TOP]




Interactions highlighted in the image:


Potential interactions (not in the image):


  • Host endoproteases (including furin) cleave HIV Env polyprotein in the highly conserved domain at the carboxy terminus, consisting of residues: Arg-X-Lys/Arg-Arg [see GUAVAh Furin interaction profile].
  • Env binds to the molecular chaperone BiP.
  • See protein-protein interactions for gp120.


Genomic Location & Protein Sequence: [TOP]

HIV-1 (HXB2)ENV:

          10         20         30         40         50         60         70         80         90        100
| | | | | | | | | |
MRVKEKYQHL WRWGWRWGTM LLGMLMICSA TEKLWVTVYY GVPVWKEATT TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLVNVT ENFNMWKNDM
110 120 130 140 150 160 170 180 190 200
| | | | | | | | | |
VEQMHEDIIS LWDQSLKPCV KLTPLCVSLK CTDLKNDTNT NSSSGRMIME KGEIKNCSFN ISTSIRGKVQ KEYAFFYKLD IIPIDNDTTS YKLTSCNTSV
210 220 230 240 250 260 270 280 290 300
| | | | | | | | | |
ITQACPKVSF EPIPIHYCAP AGFAILKCNN KTFNGTGPCT NVSTVQCTHG IRPVVSTQLL LNGSLAEEEV VIRSVNFTDN AKTIIVQLNT SVEINCTRPN
310 320 330 340 350 360 370 380 390 400
| | | | | | | | | |
NNTRKRIRIQ RGPGRAFVTI GKIGNMRQAH CNISRAKWNN TLKQIASKLR EQFGNNKTII FKQSSGGDPE IVTHSFNCGG EFFYCNSTQL FNSTWFNSTW
410 420 430 440 450 460 470 480 490 500
| | | | | | | | | |
STEGSNNTEG SDTITLPCRI KQIINMWQKV GKAMYAPPIS GQIRCSSNIT GLLLTRDGGN SNNESEIFRP GGGDMRDNWR SELYKYKVVK IEPLGVAPTK
510 520 530 540 550 560 570 580 590 600
| | | | | | | | | |
AKRRVVQREK RAVGIGALFL GFLGAAGSTM GAASMTLTVQ ARQLLSGIVQ QQNNLLRAIE AQQHLLQLTV WGIKQLQARI LAVERYLKDQ QLLGIWGCSG
610 620 630 640 650 660 670 680 690 700
| | | | | | | | | |
KLICTTAVPW NASWSNKSLE QIWNHTTWME WDREINNYTS LIHSLIEESQ NQQEKNEQEL LELDKWASLW NWFNITNWLW YIKLFIMIVG GLVGLRIVFA
710 720 730 740 750 760 770 780 790 800
| | | | | | | | | |
VLSIVNRVRQ GYSPLSFQTH LPTPRGPDRP EGIEEEGGER DRDRSIRLVN GSLALIWDDL RSLCLFSYHR LRDLLLIVTR IVELLGRRGW EALKYWWNLL
810 820 830 840 850
| | | | |
QYWSQELKNS AVSLLNATAI AVAEGTDRVI EVVQGACRAI RHIPRRIRQG LERILL
[download in fasta format] Please note that Cys119 and Cys 205 disulfide bond are marked in bold and underlined.

Length: 856 amino acids
Molecular Weight: 97212 Da
Theoretical pI: 9.17


Protein Domains/Folds/Motifs: [TOP]

InterPro signature for gp41 - IPR000328

InterPro signature for gp120 - IPR000777


Secondary Structure prediction:

Transmembrane Regions - tmhmm:


Coiled Coil Regions - ncoils:


Low Complexity Regions - seg:


Antigenic Sites - EMBOSS:


Signal peptide Region (residues 1 - 30)
MRVKEKYQHL WRWGWRWGTM LLGMLMICSA

gp120 Region (residues 31 - 511)


gp41 Region (residues 512 - 856)



Predicted Motifs: Printer-friendly version

N-glycosylation:
N-myristoylation:
Amidation:
Protein kinase C:
Casein kinase II:
Tyrosine kinase:
cAMP / cGMP kinase:
Cell attachment motif:
Asp Protease motif:
Asp Prot Retro motif:
Cysteine-rich Region:
Tryptophan-rich Region:
Zinc-finger CCHC motif:
Leucine Zipper motif:

HIV Antiretrovirals and Drug Resistance Mutations: [TOP]

See Stanford University HIV Drug Resistance Database


See ViralZone HIV Drug Pages


Mechanism of Action:


Viral entry describes a complex process that involves various steps, including the fusion of the viral membrane to the host cellular membrane.
Currently, there is only one fusion inhibitor that has been approved for HIV treatment, Enfuviritide.
This 36 amino acid polypeptide binds to the haptad repeat (HR) regions of the gp41 viral protein and engages in a coil-coil interaction.
This interaction prevents the virus particle from attaching to the host cell membrane and thus, prevents the entry and infection of HIV.


Drug Resistance Mutations:


Fusion Inhibitor:
Position Mutation Additional Information Drugs Affected Reference
G36 D, E, V, S G36D/E mutations are associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
I37 V Enfuviritide
V38 E, A, M, G V38E/A mutations are associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
Q40 H Mutation is associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
N42 T, S N42S occurs in ~15% of viruses from Enfuviritide-naive patients and does not decrease drug susceptibility. Enfuviritide
N43 D, K, S N43D mutation is associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
L44 M Enfuviritide
L45 M Enfuviritide
Primary and Secondary Database Entries: [TOP]

Identifiers:



ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB/MMDB: Search for HIV-1 & Env

UniProt: P04578 (HIV-1 HXB2 ENV)
EMBL: K03455; AAB50262.1 [EMBL/GenBank/DDBJ]

InterPro: IPR000328 - gp41 family / IPR000777 - gp120 family
Pfam: PF00517 - gp41 family / PF00516 - gp120 family
Prints: none
SCOP: SSF56502 - gp120 core / SSF52440 - preATP-grasp domain / SSF56349 - DNA breaking-rejoining motif
BLOCKS: P04578
Prosite: P04578
ProtoNet: P04578
Database of Interacting Proteins: P04578
ModBase: P04578
HIV-1/Human Protein Interaction DB: HIV-1 Env
HIV-1 Sequence Database Los Alamos HIV Sequence Database

PDB:




Reviews and References: [TOP]

Cite the resource by citing the following paper:
Doherty R et al. BioAfrica's HIV-1 Proteomics Resource: Combining protein data with bioinformatics tools. Retrovirology (2005), 9;2(1):18.

1 - HIV Sequence Compendium 2000
Kuiken CL, Foley B, Hahn B, Korber B, Marx PA, McCutchan F, Mellors JW, Mullins JI, Sodroski J, Wolinksy S.
Theoretical Biol. & Biophys. Group, Los Alamos Nat Lab, LA-UR 01-3860 [Read it online: Compendium]
2 - Retroviruses
Coffin JM, Hughes SH, Varmus HE.
CD-ROM ed. (2002) Cold Spring Harbor Laboratory Press [Read it online: NCBI Bookshelf]
3 - The CD4-gp120 interaction and AIDS pathogenesis.
Capon DJ, Ward RH.
Annu Rev Immunol. 9: 649-678 (1991) [pubmed: 1910691]
4 - Maturation of HIV envelope glycoprotein precursors by cellular endoproteases
Moulard M, Decroly E.
Biochim Biophys Acta 1469(3): 121-132 (2000) [pubmed: 11063880]
5 - Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study.
Shepherd JC1, Jacobson LP, Qiao W, Jamieson BD, Phair JP, Piazza P, Quinn TC, Margolick JB.
J Infect Dis. 198(8):1104-12 (2008) [pubmed: 18783316]
6 - Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule.
McDougal JS, Kennedy MS, Sligh JM, Cort SP, Mawle A, Nicholson JK.
Science 231(4736):382-5 (1986) [pubmed: 3001934]
7 - CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5.
Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J.
Nature 384(6605):179-83 (1996) [pubmed: 8906795]
8 - Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.
Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, Heneine W, Kantor R, Jordan MR, Schapiro JM, Vandamme AM, Sandstrom P, Boucher CA, van de Vijver D, Rhee SY, Liu TF, Pillay D, Shafer RW.
PLoS One 4(3):e4724 (2009) [pubmed: 19266092]
9 - Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2.
Melby T, Sista P, DeMasi R, Kirkland T, Roberts N, Salgo M, Heilek-Snyder G, Cammack N, Matthews TJ, Greenberg ML.
AIDS Res Hum Retroviruses 22(5):375-85 (2006) [pubmed: 16706613]



Thanks to ViralZone at the Swiss Institute of Bioinformatics (SIB) for allowing the use of their images on bioafrica.net.
Page last updated by Megan Druce, Paula Sommer and Tulio de Oliveira (UKZN/Africa Centre) & Philippe Le Mercier, Chantal Hulo and Patrick Masson (SIB/ViralZone).