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Protein

Envelope glycoprotein gp160

Gene

env

Organism
Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI) (HIV-1)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Envelope glycoprotein gp160: Oligomerizes in the host endoplasmic reticulum into predominantly trimers. In a second time, gp160 transits in the host Golgi, where glycosylation is completed. The precursor is then proteolytically cleaved in the trans-Golgi and thereby activated by cellular furin or furin-like proteases to produce gp120 and gp41.UniRule annotation
Surface protein gp120: Attaches the virus to the host lymphoid cell by binding to the primary receptor CD4. This interaction induces a structural rearrangement creating a high affinity binding site for a chemokine coreceptor like CXCR4 and/or CCR5. Acts as a ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses. These interactions allow capture of viral particles at mucosal surfaces by these cells and subsequent transmission to permissive cells. HIV subverts the migration properties of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus transmission to permissive T-cells occurs either in trans (without DCs infection, through viral capture and transmission), or in cis (following DCs productive infection, through the usual CD4-gp120 interaction), thereby inducing a robust infection. In trans infection, bound virions remain infectious over days and it is proposed that they are not degraded, but protected in non-lysosomal acidic organelles within the DCs close to the cell membrane thus contributing to the viral infectious potential during DCs' migration from the periphery to the lymphoid tissues. On arrival at lymphoid tissues, intact virions recycle back to DCs' cell surface allowing virus transmission to CD4+ T-cells.UniRule annotation
Transmembrane protein gp41: Acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During fusion of viral and target intracellular membranes, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Complete fusion occurs in host cell endosomes and is dynamin-dependent, however some lipid transfer might occur at the plasma membrane. The virus undergoes clathrin-dependent internalization long before endosomal fusion, thus minimizing the surface exposure of conserved viral epitopes during fusion and reducing the efficacy of inhibitors targeting these epitopes. Membranes fusion leads to delivery of the nucleocapsid into the cytoplasm.UniRule annotation

Miscellaneous

Inhibitors targeting HIV-1 viral envelope proteins are used as antiretroviral drugs. Attachment of virions to the cell surface via non-specific interactions and CD4 binding can be blocked by inhibitors that include cyanovirin-N, cyclotriazadisulfonamide analogs, PRO 2000, TNX 355 and PRO 542. In addition, BMS 806 can block CD4-induced conformational changes. Env interactions with the coreceptor molecules can be targeted by CCR5 antagonists including SCH-D, maraviroc (UK 427857) and aplaviroc (GW 873140), and the CXCR4 antagonist AMD 070. Fusion of viral and cellular membranes can be inhibited by peptides such as enfuvirtide and tifuvirtide (T 1249). Resistance to inhibitors associated with mutations in Env are observed. Most of the time, single mutations confer only a modest reduction in drug susceptibility. Combination of several mutations is usually required to develop a high-level drug resistance.UniRule annotation
HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K).UniRule annotation

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processApoptosis, Clathrin-mediated endocytosis of virus by host, Fusion of virus membrane with host endosomal membrane, Fusion of virus membrane with host membrane, Host-virus interaction, Viral attachment to host cell, Viral immunoevasion, Viral penetration into host cytoplasm, Virus endocytosis by host, Virus entry into host cell

Enzyme and pathway databases

ReactomeiR-HSA-5621480. Dectin-2 family.

Names & Taxonomyi

Protein namesi
Recommended name:
Envelope glycoprotein gp160UniRule annotation
Alternative name(s):
Env polyproteinUniRule annotation
Cleaved into the following 2 chains:
Surface protein gp120UniRule annotation
Short name:
SUUniRule annotation
Alternative name(s):
Glycoprotein 120UniRule annotation
Short name:
gp120UniRule annotation
Transmembrane protein gp41UniRule annotation
Short name:
TMUniRule annotation
Alternative name(s):
Glycoprotein 41UniRule annotation
Short name:
gp41UniRule annotation
Gene namesi
Name:envUniRule annotation
OrganismiHuman immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI) (HIV-1)
Taxonomic identifieri11686 [NCBI]
Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostiHomo sapiens (Human) [TaxID: 9606]
Proteomesi
  • UP000007692 Componenti: Genome

Subcellular locationi

Surface protein gp120 :
  • Virion membrane UniRule annotation; Peripheral membrane protein UniRule annotation
  • Host cell membrane UniRule annotation; Peripheral membrane protein UniRule annotation
  • Host endosome membrane UniRule annotation; Single-pass type I membrane protein UniRule annotation
  • Note: The surface protein is not anchored to the viral envelope, but associates with the extravirion surface through its binding to TM. It is probably concentrated at the site of budding and incorporated into the virions possibly by contacts between the cytoplasmic tail of Env and the N-terminus of Gag.UniRule annotation
Transmembrane protein gp41 :
  • Virion membrane UniRule annotation; Single-pass type I membrane protein UniRule annotation
  • Host cell membrane UniRule annotation; Single-pass type I membrane protein UniRule annotation
  • Host endosome membrane UniRule annotation; Single-pass type I membrane protein UniRule annotation
  • Note: It is probably concentrated at the site of budding and incorporated into the virions possibly by contacts between the cytoplasmic tail of Env and the N-terminus of Gag.UniRule annotation

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini33 – 689ExtracellularUniRule annotationAdd BLAST657
Transmembranei690 – 710HelicalUniRule annotationAdd BLAST21
Topological domaini711 – 861CytoplasmicUniRule annotationAdd BLAST151

GO - Cellular componenti

Keywords - Cellular componenti

Host cell membrane, Host endosome, Host membrane, Membrane, Viral envelope protein, Virion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi184 – 185LD → AA: Partial loss of CD4-independent binding. 1 Publication2
Mutagenesisi769C → F: Almost no effect on virions assembly and infectivity. 1 Publication1

Keywords - Diseasei

AIDS

Chemistry databases

ChEMBLiCHEMBL5826.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 32UniRule annotationAdd BLAST32
ChainiPRO_000023947433 – 861Envelope glycoprotein gp160UniRule annotationAdd BLAST829
ChainiPRO_000003838833 – 516Surface protein gp120UniRule annotationAdd BLAST484
ChainiPRO_0000038389517 – 861Transmembrane protein gp41UniRule annotationAdd BLAST345

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi54 ↔ 74UniRule annotation1 Publication
Glycosylationi88N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi119 ↔ 210UniRule annotation1 Publication
Disulfide bondi126 ↔ 201UniRule annotation1 Publication
Disulfide bondi131 ↔ 162UniRule annotation1 Publication
Glycosylationi136N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi141N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi146N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi161N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi165N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi191N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi202N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi223 ↔ 252UniRule annotation1 Publication
Disulfide bondi233 ↔ 244UniRule annotation1 Publication
Glycosylationi235N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi239N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi246N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi267N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi281N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi294N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi300N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi301 ↔ 336UniRule annotation1 Publication
Glycosylationi306N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi337N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi344N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi361N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi383 ↔ 450UniRule annotation1 Publication
Disulfide bondi390 ↔ 423UniRule annotation1 Publication
Glycosylationi391N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi397N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi402N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi411N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi453N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi468N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi603 ↔ 609UniRule annotation1 Publication
Glycosylationi616N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi621N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi630N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi642N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi679N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Lipidationi769S-palmitoyl cysteine; by hostUniRule annotation1
Lipidationi842S-palmitoyl cysteine; by hostUniRule annotation1

Post-translational modificationi

Highly glycosylated by host. The high number of glycan on the protein is reffered to as 'glycan shield' because it contributes to hide protein sequence from adaptive immune system.UniRule annotation
Palmitoylation of the transmembrane protein and of Env polyprotein (prior to its proteolytic cleavage) is essential for their association with host cell membrane lipid rafts. Palmitoylation is therefore required for envelope trafficking to classical lipid rafts, but not for viral replication.UniRule annotation1 Publication
Specific enzymatic cleavages in vivo yield mature proteins. Envelope glycoproteins are synthesized as a inactive precursor that is heavily N-glycosylated and processed likely by host cell furin in the Golgi to yield the mature SU and TM proteins. The cleavage site between SU and TM requires the minimal sequence [KR]-X-[KR]-R. About 2 of the 9 disulfide bonds of gp41 are reduced by P4HB/PDI, following binding to CD4 receptor.UniRule annotation2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei516 – 517Cleavage; by host furinUniRule annotation2

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Lipoprotein, Palmitate

Interactioni

Subunit structurei

The mature envelope protein (Env) consists of a homotrimer of non-covalently associated gp120-gp41 heterodimers. The resulting complex protrudes from the virus surface as a spike. There seems to be as few as 10 spikes on the average virion. Surface protein gp120 interacts with host CD4, CCR5 and CXCR4. Gp120 also interacts with the C-type lectins CD209/DC-SIGN and CLEC4M/DC-SIGNR (collectively referred to as DC-SIGN(R)). Gp120 and gp41 interact with GalCer. Gp120 interacts with host ITGA4/ITGB7 complex; on CD4+ T-cells, this interaction results in rapid activation of integrin ITGAL/LFA-1, which facilitates efficient cell-to-cell spreading of HIV-1. Gp120 interacts with cell-associated heparan sulfate; this interaction increases virus infectivity on permissive cells and may be involved in infection of CD4- cells.UniRule annotation4 Publications

Protein-protein interaction databases

IntActiP03377. 1 interactor.

Chemistry databases

BindingDBiP03377.

Structurei

Secondary structure

1861
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi311 – 314Combined sources4
Beta strandi322 – 325Combined sources4
Helixi559 – 594Combined sources36
Helixi633 – 655Combined sources23

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1ENVX-ray2.60A546-593[»]
A633-670[»]
1ERFinfrared-A517-539[»]
1FAVX-ray3.00A546-595[»]
C639-670[»]
1P5Ainfrared-A517-539[»]
1U6UNMR-A310-326[»]
1U6VNMR-A310-326[»]
2ZZOX-ray2.20C633-666[»]
N551-586[»]
3G9RX-ray2.00A/B/C/D/E/F667-689[»]
3MNWX-ray2.20P657-676[»]
3VGXX-ray1.74C558-595[»]
D626-657[»]
3VTPX-ray1.90C555-595[»]
D631-666[»]
ProteinModelPortaliP03377.
SMRiP03377.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP03377.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni131 – 161V1UniRule annotationAdd BLAST31
Regioni162 – 201V2UniRule annotationAdd BLAST40
Regioni301 – 335V3UniRule annotationAdd BLAST35
Regioni369 – 379CD4-binding loopUniRule annotationAdd BLAST11
Regioni390 – 423V4UniRule annotationAdd BLAST34
Regioni466 – 476V5Add BLAST11
Regioni468 – 476V5UniRule annotation9
Regioni517 – 537Fusion peptideUniRule annotationAdd BLAST21
Regioni579 – 597ImmunosuppressionUniRule annotationAdd BLAST19
Regioni667 – 688MPER; binding to GalCerUniRule annotationAdd BLAST22

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili638 – 672UniRule annotationAdd BLAST35

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi184 – 186Putative binding site to alpha-4/beta-7 integrin3
Motifi717 – 720YXXL motif; contains endocytosis signalUniRule annotation4
Motifi860 – 861Di-leucine internalization motifUniRule annotation2

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi465 – 468Poly-Asn4

Domaini

Some of the most genetically diverse regions of the viral genome are present in Env. They are called variable regions 1 through 5 (V1 through V5). Coreceptor usage of gp120 is determined mainly by the primary structure of the third variable region (V3) in the outer domain of gp120. The sequence of V3 determines which coreceptor, CCR5 and/or CXCR4 (corresponding to R5/macrophage, X4/T cell and R5X4/T cell and macrophage tropism), is used to trigger the fusion potential of the Env complex, and hence which cells the virus can infect. Binding to CCR5 involves a region adjacent in addition to V3.UniRule annotation
The membrane proximal external region (MPER) present in gp41 is a tryptophan-rich region recognized by the antibodies 2F5, Z13, and 4E10. MPER seems to play a role in fusion.UniRule annotation
The 17 amino acids long immunosuppressive region is present in many retroviral envelope proteins. Synthetic peptides derived from this relatively conserved sequence inhibit immune function in vitro and in vivo.UniRule annotation
The YXXL motif is involved in determining the exact site of viral release at the surface of infected mononuclear cells and promotes endocytosis. YXXL and di-leucine endocytosis motifs interact directly or indirectly with the clathrin adapter complexes, opperate independently, and their activities are not additive.UniRule annotation
The CD4-binding region is targeted by the antibody b12.UniRule annotation

Sequence similaritiesi

Belongs to the HIV-1 env protein family.UniRule annotation

Keywords - Domaini

Coiled coil, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

OrthoDBiVOG09000036.

Family and domain databases

CDDicd09909. HIV-1-like_HR1-HR2. 1 hit.
Gene3Di2.170.40.20. 2 hits.
HAMAPiMF_04083. HIV_ENV. 1 hit.
InterProiView protein in InterPro
IPR036377. Gp120_core_sf.
IPR000328. GP41-like.
IPR000777. HIV1_Gp120.
PfamiView protein in Pfam
PF00516. GP120. 1 hit.
PF00517. GP41. 1 hit.
SUPFAMiSSF56502. SSF56502. 3 hits.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P03377-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRVKEKYQHL WRWGWKWGTM LLGILMICSA TEKLWVTVYY GVPVWKEATT
60 70 80 90 100
TLFCASDAKA YDTEVHNVWA THACVPTDPN PQEVVLVNVT ENFNMWKNDM
110 120 130 140 150
VEQMHEDIIS LWDQSLKPCV KLTPLCVSLK CTDLGNATNT NSSNTNSSSG
160 170 180 190 200
EMMMEKGEIK NCSFNISTSI RGKVQKEYAF FYKLDIIPID NDTTSYTLTS
210 220 230 240 250
CNTSVITQAC PKVSFEPIPI HYCAPAGFAI LKCNNKTFNG TGPCTNVSTV
260 270 280 290 300
QCTHGIRPVV STQLLLNGSL AEEEVVIRSA NFTDNAKTII VQLNQSVEIN
310 320 330 340 350
CTRPNNNTRK SIRIQRGPGR AFVTIGKIGN MRQAHCNISR AKWNATLKQI
360 370 380 390 400
ASKLREQFGN NKTIIFKQSS GGDPEIVTHS FNCGGEFFYC NSTQLFNSTW
410 420 430 440 450
FNSTWSTEGS NNTEGSDTIT LPCRIKQFIN MWQEVGKAMY APPISGQIRC
460 470 480 490 500
SSNITGLLLT RDGGNNNNGS EIFRPGGGDM RDNWRSELYK YKVVKIEPLG
510 520 530 540 550
VAPTKAKRRV VQREKRAVGI GALFLGFLGA AGSTMGARSM TLTVQARQLL
560 570 580 590 600
SGIVQQQNNL LRAIEAQQHL LQLTVWGIKQ LQARILAVER YLKDQQLLGI
610 620 630 640 650
WGCSGKLICT TAVPWNASWS NKSLEQIWNN MTWMEWDREI NNYTSLIHSL
660 670 680 690 700
IEESQNQQEK NEQELLELDK WASLWNWFNI TNWLWYIKIF IMIVGGLVGL
710 720 730 740 750
RIVFAVLSIV NRVRQGYSPL SFQTHLPTPR GPDRPEGIEE EGGERDRDRS
760 770 780 790 800
IRLVNGSLAL IWDDLRSLCL FSYHRLRDLL LIVTRIVELL GRRGWEALKY
810 820 830 840 850
WWNLLQYWSQ ELKNSAVSLL NATAIAVAEG TDRVIEVVQG ACRAIRHIPR
860
RIRQGLERIL L
Length:861
Mass (Da):97,488
Last modified:July 21, 1986 - v1
Checksum:i04DE2B4D4E4FD63A
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti135 – 137GNA → KND in strain: Clone pNL4-3. 3
Natural varianti143 – 147Missing in strain: Clone pNL4-3. 5
Natural varianti151 – 153EMM → RMI in strain: Clone pNL4-3. 3
Natural varianti172G → D in strain: Clone pNL4-3. 1
Natural varianti187I → V in strain: Clone pNL4-3. 1
Natural varianti192 – 193Missing in strain: Clone pNL4-3. 2
Natural varianti197 – 199TLT → RLI in strain: Clone pNL4-3. 3
Natural varianti274E → D in strain: Clone pNL4-3. 1
Natural varianti295Q → T in strain: Clone pNL4-3. 1
Natural varianti538R → A in strain: Clone pNL4-3. 1
Natural varianti552G → D in strain: Clone pNL4-3. 1
Natural varianti689I → L in strain: Clone pNL4-3. 1
Natural varianti728T → I in strain: Clone pNL4-3. 1
Natural varianti818S → N in strain: Clone pNL4-3. 1
Natural varianti838 – 842VQGAC → LQAAY in strain: Clone pNL4-3. 5

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K02013 Genomic RNA. Translation: AAB59751.1.
A04321 Unassigned RNA. Translation: CAA00352.1.
M19921 Genomic RNA. Translation: AAA44992.2.
PIRiA03975. VCLJLV.

Similar proteinsi

Entry informationi

Entry nameiENV_HV1BR
AccessioniPrimary (citable) accession number: P03377
Secondary accession number(s): Q85582
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: July 21, 1986
Last modified: November 22, 2017
This is version 150 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families