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Protein

Envelope glycoprotein gp160

Gene

env

Organism
Human immunodeficiency virus type 1 group M subtype D (isolate Z6) (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 D (isolate Z6) (HIV-1)
Taxonomic identifieri11708 [NCBI]
Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostiHomo sapiens (Human) [TaxID: 9606]

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 domaini32 – 683ExtracellularUniRule annotationAdd BLAST652
Transmembranei684 – 704HelicalUniRule annotationAdd BLAST21
Topological domaini705 – 855CytoplasmicUniRule annotationAdd BLAST151

GO - Cellular componenti

Keywords - Cellular componenti

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

Pathology & Biotechi

Keywords - Diseasei

AIDS

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 31UniRule annotationAdd BLAST31
ChainiPRO_000044124732 – 855Envelope glycoprotein gp160UniRule annotationAdd BLAST824
ChainiPRO_000044124832 – 510Surface protein gp120UniRule annotationAdd BLAST479
ChainiPRO_0000038432511 – 855Transmembrane protein gp41UniRule annotationAdd BLAST345

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi53 ↔ 73UniRule annotation
Glycosylationi87N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi118 ↔ 207UniRule annotation
Disulfide bondi125 ↔ 198UniRule annotation
Glycosylationi129N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi130 ↔ 155UniRule annotation
Glycosylationi140N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi145N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi154N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi158N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi186N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi189N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi199N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi220 ↔ 249UniRule annotation
Disulfide bondi230 ↔ 241UniRule annotation
Glycosylationi236N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi243N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi264N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi278N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi291N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi297N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi298 ↔ 332UniRule annotation
Glycosylationi333N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi340N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi355N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi378 ↔ 444UniRule annotation
Disulfide bondi385 ↔ 417UniRule annotation
Glycosylationi386N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi392N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi398N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi404N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi443N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi447N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi460N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi461N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi464N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Disulfide bondi597 ↔ 603UniRule annotation
Glycosylationi610N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi615N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi624N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi636N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Glycosylationi673N-linked (GlcNAc...) asparagine; by hostUniRule annotation1
Lipidationi763S-palmitoyl cysteine; by hostUniRule annotation1

Post-translational modificationi

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 annotation
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 annotation

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei510 – 511Cleavage; by host furinUniRule annotation2

Keywords - PTMi

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

Proteomic databases

PRIDEiP04580.

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 annotation

Protein-protein interaction databases

IntActiP04580. 1 interactor.
MINTiMINT-1523040.

Structurei

Secondary structure

1855
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi551 – 588Combined sources38
Turni664 – 667Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1TJHX-ray2.10P659-669[»]
1TJIX-ray2.20P653-669[»]
3F4YX-ray2.00A/B/C545-580[»]
3F50X-ray2.80A545-580[»]
3G7AX-ray2.80A545-580[»]
3MOAX-ray2.30P653-669[»]
3MOBX-ray2.60P659-669[»]
3MODX-ray2.20P659-669[»]
4I2LX-ray1.43C549-589[»]
ProteinModelPortaliP04580.
SMRiP04580.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP04580.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni130 – 154V1UniRule annotationAdd BLAST25
Regioni155 – 198V2UniRule annotationAdd BLAST44
Regioni298 – 331V3UniRule annotationAdd BLAST34
Regioni364 – 374CD4-binding loopUniRule annotationAdd BLAST11
Regioni385 – 417V4UniRule annotationAdd BLAST33
Regioni459 – 470V5Add BLAST12
Regioni462 – 470V5UniRule annotation9
Regioni511 – 531Fusion peptideUniRule annotationAdd BLAST21
Regioni573 – 591ImmunosuppressionUniRule annotationAdd BLAST19
Regioni661 – 682MPER; binding to GalCerUniRule annotationAdd BLAST22

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili632 – 666UniRule annotationAdd BLAST35

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi711 – 714YXXL motif; contains endocytosis signalUniRule annotation4
Motifi854 – 855Di-leucine internalization motifUniRule annotation2

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

Family and domain databases

CDDicd09909. HIV-1-like_HR1-HR2. 1 hit.
HAMAPiMF_04083. HIV_ENV. 1 hit.
InterProiView protein in InterPro
IPR000328. GP41-like.
IPR000777. HIV1_GP160.
PfamiView protein in Pfam
PF00516. GP120. 2 hits.
PF00517. GP41. 1 hit.
SUPFAMiSSF56502. SSF56502. 2 hits.

Sequencei

Sequence statusi: Complete.

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

P04580-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRAREIERNC PNLWKWGIML LGILMICSAA DNLWVTVYYG VPVWKEATTT
60 70 80 90 100
LFCASDAKSY KTEAHNIWAT HACVPTDPNP QEIELENVTE NFNMWRNNMV
110 120 130 140 150
EQIHEDIISL WDQSLKPCVK LTPLCVTLNC TDESDEWMGN VTGKNVTEDI
160 170 180 190 200
RMKNCSFNIT TVVRDKTKQV HALFYRLDIV PIDNDNSTNS TNYRLINCNT
210 220 230 240 250
SAITQACPKV SFEPIPIHYC APAGFAILKC RDKRFNGTGP CTNVSTVQCT
260 270 280 290 300
HGIRPVVSTQ LLLNGSLAEE EIIIRSENLT NNAKIIIVQL NESVAINCTR
310 320 330 340 350
PYKNTRQSTP IGLGQALYTT RGRTKIIGQA HCNISKEDWN KTLQRVAIKL
360 370 380 390 400
GNLLNKTTII FKPSSGGDAE ITTHSFNCGG EFFYCNTSGL FNSTWNINNS
410 420 430 440 450
EGANSTESDN KLITLQCRIK QIINMWQGVG KAMYAPPIEG QINCSSNITG
460 470 480 490 500
LLLTRDGGTN NSSNETFRPG GGDMRDNWRS ELYKYKVVKI EPLGVAPTKA
510 520 530 540 550
KRRVVEREKR AIGLGAMFLG FLGAAGSTMG AASVTLTVQA RQLMSGIVQQ
560 570 580 590 600
QNNLLRAIEA QQHLLQLTVW GIKQLQARIL AVERYLKDQQ LLGIWGCSGK
610 620 630 640 650
LICTTTVPWN SSWSNRSLND IWQNMTWMEW EREIDNYTGL IYRLIEESQT
660 670 680 690 700
QQEKNEQELL ELDKWASLWN WFNITQWLWY IKIFIMIVGG LIGLRIVFAV
710 720 730 740 750
LSLVNRVRQG YSPLSFQTLL PAPREPDRPE GIEEEGGERG RDRSIRLVNG
760 770 780 790 800
FSALIWDDLR NLCLFSYHRL RDLILIAARI VELLGRRGWE ALKYLWNLLQ
810 820 830 840 850
YWSRELRNSA SSLLDTIAIA VAEGTDRVIE IVRRTYRAVL NVPTRIRQGL

ERLLL
Length:855
Mass (Da):96,971
Last modified:August 13, 1987 - v1
Checksum:i3B4D3D6E239C3457
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
K03458 Genomic RNA. Translation: AAA45380.1.
PIRiD26192. VCLJZR.

Similar proteinsi

Entry informationi

Entry nameiENV_HV1Z6
AccessioniPrimary (citable) accession number: P04580
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: August 13, 1987
Last modified: September 27, 2017
This is version 132 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

Documents

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