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HAMAP rule MF_04083

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General rule information [?]

Accession MF_04083
Dates 8-JUN-2017 (Created)
29-SEP-2022 (Last updated, Version 11)
Viruses; Lentivirus
Template P04578 (ENV_HV1H2)

Propagated annotation [?]

Identifier, protein and gene names [?]

Protein name
RecName: Full=Envelope glycoprotein gp160;
AltName: Full=Env polyprotein;
RecName: Full=Surface protein gp120;
AltName: Full=Glycoprotein 120;
RecName: Full=Transmembrane protein gp41;
AltName: Full=Glycoprotein 41;
Flags: Precursor;
Gene name

Comments [?]

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.
Subunit 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.
Subcellular location 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.
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.
Domain 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 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 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.
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.
Ptm 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.
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.
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.
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).
Similarity Belongs to the HIV-1 env protein family.

Keywords [?]

Gene Ontology [?]

GO:0044175; Cellular component: host cell endosome membrane.
GO:0020002; Cellular component: host cell plasma membrane.
GO:0016020; Cellular component: membrane.
GO:0055036; Cellular component: virion membrane.
GO:0005198; Molecular function: structural molecule activity.
GO:0090527; Biological process: actin filament reorganization.
GO:0075512; Biological process: clathrin-dependent endocytosis of virus by host cell.
GO:0019049; Biological process: mitigation of host antiviral defense response.
GO:0039654; Biological process: fusion of virus membrane with host endosome membrane.
GO:0019064; Biological process: fusion of virus membrane with host plasma membrane.
GO:1903905; Biological process: positive regulation of establishment of T cell polarity.
GO:1903908; Biological process: positive regulation of plasma membrane raft polarization.
GO:1903911; Biological process: positive regulation of receptor clustering.
GO:0019082; Biological process: viral protein processing.
GO:0019062; Biological process: virion attachment to host cell.

Cross-references [?]

PROSITE PS00001; ASN_GLYCOSYLATION; 0-unlimited; trigger=PRU00498;
Pfam PF00516; GP120; 1;
PF00517; GP41; 1;

Features [?]

From: ENV_HV1H2 (P04578)
Key     From     To       Description   Tag   Condition   FTGroup
SIGNAL     Nter     32                
CHAIN     33     Cter       Envelope glycoprotein gp160        
CHAIN     33     511       Surface protein gp120        
CHAIN     512     Cter       Transmembrane protein gp41        
TOPO_DOM     33     684       Extracellular        
TRANSMEM     685     705       Helical        
TOPO_DOM     706     Cter       Cytoplasmic        
REGION     131     156       V1        
REGION     157     196       V2        
REGION     296     330       V3        
REGION     364     374       CD4-binding loop        
REGION     385     418       V4        
REGION     461     471       V5        
REGION     512     532       Fusion peptide        
REGION     574     592       Immunosuppression        
REGION     662     683       MPER; binding to GalCer        
COILED     633     667                
MOTIF     712     715       YXXL motif; contains endocytosis signal     Y-x(2)-L  
MOTIF     Cter-1     Cter       Di-leucine internalization motif     L-L  
SITE     511     512       Cleavage; by host furin        
LIPID     764     764       S-palmitoyl cysteine; by host     C  
LIPID     837     837       S-palmitoyl cysteine; by host     C  
DISULFID     54     74             C-x*-C  
DISULFID     119     205             C-x*-C  
DISULFID     126     196             C-x*-C  
DISULFID     131     157             C-x*-C  
DISULFID     218     247             C-x*-C  
DISULFID     228     239             C-x*-C  
DISULFID     296     331             C-x*-C  
DISULFID     378     445             C-x*-C  
DISULFID     385     418             C-x*-C  
DISULFID     598     604             C-x*-C  

Additional information [?]

Size range 832-876 amino acids
Related rules None
Fusion None