P04624 · ENV_HV1H3

Function

function

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.

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.

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.

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.
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).

Features

Showing features for site.

TypeIDPosition(s)Description
Site511-512Cleavage; by host furin

GO annotations

AspectTerm
Cellular Componenthost cell endosome membrane
Cellular Componenthost cell plasma membrane
Cellular Componentmembrane
Cellular Componentviral envelope
Cellular Componentvirion membrane
Molecular Functionstructural molecule activity
Biological Processapoptotic process
Biological Processclathrin-dependent endocytosis of virus by host cell
Biological Processfusion of virus membrane with host endosome membrane
Biological Processfusion of virus membrane with host plasma membrane
Biological Processpositive regulation of establishment of T cell polarity
Biological Processpositive regulation of plasma membrane raft polarization
Biological Processpositive regulation of receptor clustering
Biological Processviral protein processing
Biological Processvirion attachment to host cell
Biological Processvirus-mediated perturbation of host defense response

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Envelope glycoprotein gp160
  • Alternative names
    • Env polyprotein
  • Cleaved into 2 chains
    • Surface protein gp120
      (SU
      ) Alternative names: Glycoprotein 120
      (gp120
      )
    • Transmembrane protein gp41
      (TM
      ) Alternative names: Glycoprotein 41
      (gp41
      )

Gene names

    • Name
      env

Organism names

Accessions

  • Primary accession
    P04624

Subcellular Location

Surface protein gp120

Virion membrane
; Peripheral membrane protein
Host cell membrane
; Peripheral membrane protein
Host endosome membrane
; Single-pass type I membrane protein
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.

Transmembrane protein gp41

Virion membrane
; Single-pass type I membrane protein
Host cell membrane
; Single-pass type I membrane protein
Host endosome membrane
; Single-pass type I membrane protein
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.

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain33-684Extracellular
Transmembrane685-705Helical
Topological domain706-856Cytoplasmic

Keywords

Phenotypes & Variants

Keywords

PTM/Processing

Features

Showing features for signal, chain, glycosylation, disulfide bond, lipidation.

TypeIDPosition(s)Description
Signal1-32
ChainPRO_000003842933-511Surface protein gp120
ChainPRO_000023949333-856Envelope glycoprotein gp160
Glycosylation88N-linked (GlcNAc...) asparagine; by host
Disulfide bond119↔205
Disulfide bond126↔196
Disulfide bond131↔157
Glycosylation136N-linked (GlcNAc...) asparagine; by host
Glycosylation141N-linked (GlcNAc...) asparagine; by host
Glycosylation156N-linked (GlcNAc...) asparagine; by host
Glycosylation160N-linked (GlcNAc...) asparagine; by host
Glycosylation186N-linked (GlcNAc...) asparagine; by host
Glycosylation197N-linked (GlcNAc...) asparagine; by host
Disulfide bond218↔247
Disulfide bond228↔239
Glycosylation230N-linked (GlcNAc...) asparagine; by host
Glycosylation234N-linked (GlcNAc...) asparagine; by host
Glycosylation241N-linked (GlcNAc...) asparagine; by host
Glycosylation262N-linked (GlcNAc...) asparagine; by host
Glycosylation276N-linked (GlcNAc...) asparagine; by host
Glycosylation289N-linked (GlcNAc...) asparagine; by host
Glycosylation295N-linked (GlcNAc...) asparagine; by host
Disulfide bond296↔331
Glycosylation301N-linked (GlcNAc...) asparagine; by host
Glycosylation332N-linked (GlcNAc...) asparagine; by host
Glycosylation339N-linked (GlcNAc...) asparagine; by host
Glycosylation356N-linked (GlcNAc...) asparagine; by host
Disulfide bond378↔445
Disulfide bond385↔418
Glycosylation386N-linked (GlcNAc...) asparagine; by host
Glycosylation392N-linked (GlcNAc...) asparagine; by host
Glycosylation397N-linked (GlcNAc...) asparagine; by host
Glycosylation406N-linked (GlcNAc...) asparagine; by host
Glycosylation448N-linked (GlcNAc...) asparagine; by host
Glycosylation463N-linked (GlcNAc...) asparagine; by host
ChainPRO_0000038430512-856Transmembrane protein gp41
Disulfide bond598↔604
Glycosylation611N-linked (GlcNAc...) asparagine; by host
Glycosylation616N-linked (GlcNAc...) asparagine; by host
Glycosylation624N-linked (GlcNAc...) asparagine; by host
Glycosylation637N-linked (GlcNAc...) asparagine; by host
Glycosylation674N-linked (GlcNAc...) asparagine; by host
Lipidation764S-palmitoyl cysteine; by host

Post-translational modification

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.
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.
Specific enzymatic cleavages in vivo yield mature proteins. Envelope glycoproteins are synthesized as an 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.

Keywords

PTM databases

Interaction

Subunit

Surface protein gp120

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. 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.

Transmembrane protein gp41

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.

Family & Domains

Features

Showing features for region, coiled coil, motif.

TypeIDPosition(s)Description
Region131-156V1
Region157-196V2
Region296-330V3
Region364-374CD4-binding loop
Region385-418V4
Region461-471V5
Region463-471V5
Region512-532Fusion peptide
Region574-592Immunosuppression
Coiled coil633-667
Region662-683MPER; binding to GalCer
Motif712-715YXXL motif; contains endocytosis signal
Region720-740Disordered
Motif855-856Di-leucine internalization motif

Domain

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.
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.
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.
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.
The CD4-binding region is targeted by the antibody b12.

Sequence similarities

Belongs to the HIV-1 env protein family.

Keywords

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    856
  • Mass (Da)
    97,189
  • Last updated
    1996-02-01 v3
  • Checksum
    3373C68BB84C1AFC
MRVKEKYQHLWRWGWRWGTMLLGMLMICSATEKLWVTVYYGVPVWKEATTTLFCASDAKAYDTEVHNVWATHAGVPTDPNPQEVVLVNVTENFNMWKNDMVEQMHEDIISLWDQSLKPCVKLTPLCVSLKCTDLKNDTNTNSSSGRMIMEKGEIKNCSFNISTSIRGKVQKEYAFFYKLDIIPIDNDTTSYTLTSCNTSVITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGTGPCTNVSTVQCTHGIRPVVSTQLLLNGSLAEEEVVIRSVNFTDNAKTIIVQLNTSVEINCTRPNNNTRKKIRIQRGPGRAFVTIGKIGNMRQAHCNISRAKWNATLKQIASKLREQFGNNKTIIFKQSSGGDPEIVTHSFNCGGEFFYCNSTQLFNSTWFNSTWSTEGSNNTEGSDTITLPCRIKQFINMWQEVGKAMYAPPISGQIRCSSNITGLLLTRDGGNNNNGSEIFRPGGGDMRDNWRSELYKYKVVKIEPLGVAPTKAKRRVVQREKRAVGIGALFLGFLGAAGSTMGAASMTLTVQARQLLSGIVQQQNNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQQLLGIWGCSGKLLCTTAVPWNASWSNKSLEQIWNHTTWMEWDREINNYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWFNITNWLWYIKLFIMIVGGLVGLRIVFAVLSVVNRVRQGYSPLSFQTHLPIPRGPDRPEGIEEEGGERDRDRSIRLVNGSLALIWDDLRSLCLFSYHRLRDLLLIVTRIVELLGRRGWEALKYWWNLLQYWSQELKNSAVSLLNATAIAVAEGTDRVIEVVQEAYRAIRHIPRRIRQGLERILL

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
M14100
EMBL· GenBank· DDBJ
AAA44679.1
EMBL· GenBank· DDBJ
Genomic RNA

Similar Proteins

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