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The annotation and conditions in this rule are derived from the following entries: P04578 (ENV_HV1H2)

If a protein meets these conditions... i

Common conditions

Special conditions

    • Subsequence at position 33 - 684 aligns to entry P04578 (individually applies "Extracellular")
    • Subsequence at position 54 - 74 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 119 - 205 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 126 - 196 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 131 - 156 aligns to entry P04578 (individually applies "V1")
    • Subsequence at position 131 - 157 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 157 - 196 aligns to entry P04578 (individually applies "V2")
    • Subsequence at position 218 - 247 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 228 - 239 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 296 - 330 aligns to entry P04578 (individually applies "V3")
    • Subsequence at position 296 - 331 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 364 - 374 aligns to entry P04578 (individually applies "CD4-binding loop")
    • Subsequence at position 378 - 445 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 385 - 418 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 385 - 418 aligns to entry P04578 (individually applies "V4")
    • Subsequence at position 461 - 471 aligns to entry P04578 (individually applies "V5")
    • Subsequence at position 511 - 512 aligns to entry P04578 (individually applies "Cleavage; by host furin")
    • Subsequence at position 512 - 532 aligns to entry P04578 (individually applies "Fusion peptide")
    • Subsequence at position 574 - 592 aligns to entry P04578 (individually applies "Immunosuppression")
    • Subsequence at position 598 - 604 aligns to "C-x*-C" in entry P04578 (individually applies "")
    • Subsequence at position 633 - 667 aligns to entry P04578 (individually applies "")
    • Subsequence at position 662 - 683 aligns to entry P04578 (individually applies "MPER; binding to GalCer")
    • Subsequence at position 706 - @CTER@ aligns to entry P04578 (individually applies "Cytoplasmic")
    • Subsequence at position 712 - 715 aligns to "Y-x(2)-L" in entry P04578 (individually applies "YXXL motif; contains endocytosis signal")
    • Subsequence at position 764 - 764 aligns to "C" in entry P04578 (individually applies "S-palmitoyl cysteine; by host")
    • Subsequence at position 837 - 837 aligns to "C" in entry P04578 (individually applies "S-palmitoyl cysteine; by host")
    • Subsequence at position @PLUS|@CTER|-1@ - @CTER@ aligns to "L-L" in entry P04578 (individually applies "Di-leucine internalization motif")

... then these annotations are applied i

Protein namei

  • Recommended name:
    Envelope glycoprotein gp160
    Alternative name(s):
    Env polyprotein

Cleaved chain(s) or included domain(s)i

  • Cleaved chain:
    Recommended name:
    Transmembrane protein gp41
    Short name:
    TM
    Alternative name(s):
    Glycoprotein 41
    Short name:
    gp41
  • Cleaved chain:
    Recommended name:
    Surface protein gp120
    Short name:
    SU
    Alternative name(s):
    Glycoprotein 120
    Short name:
    gp120

Gene namei

  • Name:env

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.

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.
  • 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 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.

Miscellaneousi

  • 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).
  • 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.

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.
  • 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.

Sequence similaritiesi

Subcellular locationi

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

Sitei

  • Cleavage; by host furin (to residues corresponding to positions 511 - 512)

Regioni

  • V1 (to residues corresponding to positions 131 - 156)
  • V2 (to residues corresponding to positions 157 - 196)
  • V3 (to residues corresponding to positions 296 - 330)
  • CD4-binding loop (to residues corresponding to positions 364 - 374)
  • V4 (to residues corresponding to positions 385 - 418)
  • V5 (to residues corresponding to positions 461 - 471)
  • Fusion peptide (to residues corresponding to positions 512 - 532)
  • Immunosuppression (to residues corresponding to positions 574 - 592)
  • MPER; binding to GalCer (to residues corresponding to positions 662 - 683)

Disulfide bondi

  • (to residues corresponding to positions 54 - 74)
  • (to residues corresponding to positions 119 - 205)
  • (to residues corresponding to positions 126 - 196)
  • (to residues corresponding to positions 131 - 157)
  • (to residues corresponding to positions 218 - 247)
  • (to residues corresponding to positions 228 - 239)
  • (to residues corresponding to positions 296 - 331)
  • (to residues corresponding to positions 378 - 445)
  • (to residues corresponding to positions 385 - 418)
  • (to residues corresponding to positions 598 - 604)

Lipidationi

  • S-palmitoyl cysteine; by host (to residues corresponding to position 764)
  • S-palmitoyl cysteine; by host (to residues corresponding to position 837)

Topological domaini

  • Extracellular (to residues corresponding to positions 33 - 684)
  • Cytoplasmic (to residues corresponding to positions 706 - @CTER@i)

Coiled coili

  • (to residues corresponding to positions 633 - 667)

Motifi

  • YXXL motif; contains endocytosis signal (to residues corresponding to positions 712 - 715)
  • Di-leucine internalization motif (to residues corresponding to positions @PLUS|@CTER|-1@i - @CTER@i)

Keywordsi

GO (Gene Ontology) termsi

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