AC   MF_04083;
DC   Protein; auto
TR   HAMAP; MF_04083; -; 1; level=0
XX
Names: HIV_ENV
XX
ID   ENV
DE   RecName: Full=Envelope glycoprotein gp160;
DE   AltName: Full=Env polyprotein;
DE   Contains:
DE     RecName: Full=Surface protein gp120;
DE              Short=SU;
DE     AltName: Full=Glycoprotein 120;
DE              Short=gp120;
DE   Contains:
DE     RecName: Full=Transmembrane protein gp41;
DE              Short=TM;
DE     AltName: Full=Glycoprotein 41;
DE              Short=gp41;
DE   Flags: Precursor;
GN   Name=env;
XX
CC   -!- FUNCTION: Envelope glycoprotein gp160: Oligomerizes in the host
CC       endoplasmic reticulum into predominantly trimers. In a second time,
CC       gp160 transits in the host Golgi, where glycosylation is completed. The
CC       precursor is then proteolytically cleaved in the trans-Golgi and
CC       thereby activated by cellular furin or furin-like proteases to produce
CC       gp120 and gp41.
CC   -!- FUNCTION: Surface protein gp120: Attaches the virus to the host
CC       lymphoid cell by binding to the primary receptor CD4. This interaction
CC       induces a structural rearrangement creating a high affinity binding
CC       site for a chemokine coreceptor like CXCR4 and/or CCR5. Acts as a
CC       ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively
CC       found on dendritic cells (DCs), and on endothelial cells of liver
CC       sinusoids and lymph node sinuses. These interactions allow capture of
CC       viral particles at mucosal surfaces by these cells and subsequent
CC       transmission to permissive cells. HIV subverts the migration properties
CC       of dendritic cells to gain access to CD4+ T-cells in lymph nodes. Virus
CC       transmission to permissive T-cells occurs either in trans (without DCs
CC       infection, through viral capture and transmission), or in cis
CC       (following DCs productive infection, through the usual CD4-gp120
CC       interaction), thereby inducing a robust infection. In trans infection,
CC       bound virions remain infectious over days and it is proposed that they
CC       are not degraded, but protected in non-lysosomal acidic organelles
CC       within the DCs close to the cell membrane thus contributing to the
CC       viral infectious potential during DCs' migration from the periphery to
CC       the lymphoid tissues. On arrival at lymphoid tissues, intact virions
CC       recycle back to DCs' cell surface allowing virus transmission to CD4+
CC       T-cells.
CC   -!- FUNCTION: Transmembrane protein gp41: Acts as a class I viral fusion
CC       protein. Under the current model, the protein has at least 3
CC       conformational states: pre-fusion native state, pre-hairpin
CC       intermediate state, and post-fusion hairpin state. During fusion of
CC       viral and target intracellular membranes, the coiled coil regions
CC       (heptad repeats) assume a trimer-of-hairpins structure, positioning the
CC       fusion peptide in close proximity to the C-terminal region of the
CC       ectodomain. The formation of this structure appears to drive apposition
CC       and subsequent fusion of viral and target cell membranes. Complete
CC       fusion occurs in host cell endosomes and is dynamin-dependent, however
CC       some lipid transfer might occur at the plasma membrane. The virus
CC       undergoes clathrin-dependent internalization long before endosomal
CC       fusion, thus minimizing the surface exposure of conserved viral
CC       epitopes during fusion and reducing the efficacy of inhibitors
CC       targeting these epitopes. Membranes fusion leads to delivery of the
CC       nucleocapsid into the cytoplasm.
CC   -!- SUBUNIT: The mature envelope protein (Env) consists of a homotrimer of
CC       non-covalently associated gp120-gp41 heterodimers. The resulting
CC       complex protrudes from the virus surface as a spike. There seems to be
CC       as few as 10 spikes on the average virion. Surface protein gp120
CC       interacts with host CD4, CCR5 and CXCR4. Gp120 also interacts with the
CC       C-type lectins CD209/DC-SIGN and CLEC4M/DC-SIGNR (collectively referred
CC       to as DC-SIGN(R)). Gp120 and gp41 interact with GalCer. Gp120 interacts
CC       with host ITGA4/ITGB7 complex; on CD4+ T-cells, this interaction
CC       results in rapid activation of integrin ITGAL/LFA-1, which facilitates
CC       efficient cell-to-cell spreading of HIV-1. Gp120 interacts with cell-
CC       associated heparan sulfate; this interaction increases virus
CC       infectivity on permissive cells and may be involved in infection of
CC       CD4- cells.
CC   -!- SUBCELLULAR LOCATION: Transmembrane protein gp41: Virion membrane;
CC       Single-pass type I membrane protein. Host cell membrane; Single-pass
CC       type I membrane protein. Host endosome membrane; Single-pass type I
CC       membrane protein. Note=It is probably concentrated at the site of
CC       budding and incorporated into the virions possibly by contacts between
CC       the cytoplasmic tail of Env and the N-terminus of Gag.
CC   -!- SUBCELLULAR LOCATION: Surface protein gp120: Virion membrane;
CC       Peripheral membrane protein. Host cell membrane; Peripheral membrane
CC       protein. Host endosome membrane; Single-pass type I membrane protein.
CC       Note=The surface protein is not anchored to the viral envelope, but
CC       associates with the extravirion surface through its binding to TM. It
CC       is probably concentrated at the site of budding and incorporated into
CC       the virions possibly by contacts between the cytoplasmic tail of Env
CC       and the N-terminus of Gag.
CC   -!- DOMAIN: The YXXL motif is involved in determining the exact site of
CC       viral release at the surface of infected mononuclear cells and promotes
CC       endocytosis. YXXL and di-leucine endocytosis motifs interact directly
CC       or indirectly with the clathrin adapter complexes, opperate
CC       independently, and their activities are not additive.
CC   -!- DOMAIN: The 17 amino acids long immunosuppressive region is present in
CC       many retroviral envelope proteins. Synthetic peptides derived from this
CC       relatively conserved sequence inhibit immune function in vitro and in
CC       vivo.
CC   -!- DOMAIN: The CD4-binding region is targeted by the antibody b12.
CC   -!- DOMAIN: The membrane proximal external region (MPER) present in gp41 is
CC       a tryptophan-rich region recognized by the antibodies 2F5, Z13, and
CC       4E10. MPER seems to play a role in fusion.
CC   -!- DOMAIN: Some of the most genetically diverse regions of the viral
CC       genome are present in Env. They are called variable regions 1 through 5
CC       (V1 through V5). Coreceptor usage of gp120 is determined mainly by the
CC       primary structure of the third variable region (V3) in the outer domain
CC       of gp120. The sequence of V3 determines which coreceptor, CCR5 and/or
CC       CXCR4 (corresponding to R5/macrophage, X4/T cell and R5X4/T cell and
CC       macrophage tropism), is used to trigger the fusion potential of the Env
CC       complex, and hence which cells the virus can infect. Binding to CCR5
CC       involves a region adjacent in addition to V3.
CC   -!- PTM: Highly glycosylated by host. The high number of glycan on the
CC       protein is reffered to as 'glycan shield' because it contributes to
CC       hide protein sequence from adaptive immune system.
CC   -!- PTM: Specific enzymatic cleavages in vivo yield mature proteins.
CC       Envelope glycoproteins are synthesized as a inactive precursor that is
CC       heavily N-glycosylated and processed likely by host cell furin in the
CC       Golgi to yield the mature SU and TM proteins. The cleavage site between
CC       SU and TM requires the minimal sequence [KR]-X-[KR]-R. About 2 of the 9
CC       disulfide bonds of gp41 are reduced by P4HB/PDI, following binding to
CC       CD4 receptor.
CC   -!- PTM: Palmitoylation of the transmembrane protein and of Env polyprotein
CC       (prior to its proteolytic cleavage) is essential for their association
CC       with host cell membrane lipid rafts. Palmitoylation is therefore
CC       required for envelope trafficking to classical lipid rafts, but not for
CC       viral replication.
CC   -!- MISCELLANEOUS: Inhibitors targeting HIV-1 viral envelope proteins are
CC       used as antiretroviral drugs. Attachment of virions to the cell surface
CC       via non-specific interactions and CD4 binding can be blocked by
CC       inhibitors that include cyanovirin-N, cyclotriazadisulfonamide analogs,
CC       PRO 2000, TNX 355 and PRO 542. In addition, BMS 806 can block CD4-
CC       induced conformational changes. Env interactions with the coreceptor
CC       molecules can be targeted by CCR5 antagonists including SCH-D,
CC       maraviroc (UK 427857) and aplaviroc (GW 873140), and the CXCR4
CC       antagonist AMD 070. Fusion of viral and cellular membranes can be
CC       inhibited by peptides such as enfuvirtide and tifuvirtide (T 1249).
CC       Resistance to inhibitors associated with mutations in Env are observed.
CC       Most of the time, single mutations confer only a modest reduction in
CC       drug susceptibility. Combination of several mutations is usually
CC       required to develop a high-level drug resistance.
CC   -!- MISCELLANEOUS: HIV-1 lineages are divided in three main groups, M (for
CC       Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast
CC       majority of strains found worldwide belong to the group M. Group O
CC       seems to be endemic to and largely confined to Cameroon and neighboring
CC       countries in West Central Africa, where these viruses represent a small
CC       minority of HIV-1 strains. The group N is represented by a limited
CC       number of isolates from Cameroonian persons. The group M is further
CC       subdivided in 9 clades or subtypes (A to D, F to H, J and K).
CC   -!- SIMILARITY: Belongs to the HIV-1 env protein family.
XX
DR   PROSITE; PS00001; ASN_GLYCOSYLATION; 0-unlimited; trigger=yes
DR   Pfam; PF00516; GP120; 1; trigger=no
DR   Pfam; PF00517; GP41; 1; trigger=no
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KW   Apoptosis
KW   Clathrin-mediated endocytosis of virus by host
KW   Cleavage on pair of basic residues
KW   Coiled coil
KW   Disulfide bond
KW   Fusion of virus membrane with host endosomal membrane
KW   Fusion of virus membrane with host membrane
KW   Glycoprotein
KW   Host cell membrane
KW   Host endosome
KW   Host membrane
KW   Host-virus interaction
KW   Lipoprotein
KW   Membrane
KW   Palmitate
KW   Signal
KW   Transmembrane
KW   Transmembrane helix
KW   Viral attachment to host cell
KW   Viral envelope protein
KW   Viral immunoevasion
KW   Viral penetration into host cytoplasm
KW   Virion
KW   Virus endocytosis by host
KW   Virus entry into host cell
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GO   GO:0044175; C:host cell endosome membrane
GO   GO:0020002; C:host cell plasma membrane
GO   GO:0016020; C:membrane
GO   GO:0055036; C:virion membrane
GO   GO:0005198; F:structural molecule activity
GO   GO:0075512; P:clathrin-dependent endocytosis of virus by host cell
GO   GO:0019049; P:virus-mediated perturbation of host defense response
GO   GO:0039654; P:fusion of virus membrane with host endosome membrane
GO   GO:0019064; P:fusion of virus membrane with host plasma membrane
GO   GO:1903905; P:positive regulation of establishment of T cell polarity
GO   GO:1903908; P:positive regulation of plasma membrane raft polarization
GO   GO:1903911; P:positive regulation of receptor clustering
GO   GO:0019082; P:viral protein processing
GO   GO:0019062; P:virion attachment to host cell
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FT   From: ENV_HV1H2 (P04578)
FT   SIGNAL          Nter..32
FT   CHAIN           33..Cter
FT                   /note="Envelope glycoprotein gp160"
FT   CHAIN           33..511
FT                   /note="Surface protein gp120"
FT   CHAIN           512..Cter
FT                   /note="Transmembrane protein gp41"
FT   TOPO_DOM        33..684
FT                   /note="Extracellular"
FT   TRANSMEM        685..705
FT                   /note="Helical"
FT   TOPO_DOM        706..Cter
FT                   /note="Cytoplasmic"
FT   REGION          131..156
FT                   /note="V1"
FT   REGION          157..196
FT                   /note="V2"
FT   REGION          296..330
FT                   /note="V3"
FT   REGION          364..374
FT                   /note="CD4-binding loop"
FT   REGION          385..418
FT                   /note="V4"
FT   REGION          461..471
FT                   /note="V5"
FT   REGION          512..532
FT                   /note="Fusion peptide"
FT   REGION          574..592
FT                   /note="Immunosuppression"
FT   REGION          662..683
FT                   /note="MPER; binding to GalCer"
FT   COILED          633..667
FT   MOTIF           712..715
FT                   /note="YXXL motif; contains endocytosis signal"
FT   Condition: Y-x(2)-L
FT   MOTIF           Cter-1..Cter
FT                   /note="Di-leucine internalization motif"
FT   Condition: L-L
FT   SITE            511..512
FT                   /note="Cleavage; by host furin"
FT   LIPID           764
FT                   /note="S-palmitoyl cysteine; by host"
FT   Condition: C
FT   LIPID           837
FT                   /note="S-palmitoyl cysteine; by host"
FT   Condition: C
FT   DISULFID        54..74
FT   Condition: C-x*-C
FT   DISULFID        119..205
FT   Condition: C-x*-C
FT   DISULFID        126..196
FT   Condition: C-x*-C
FT   DISULFID        131..157
FT   Condition: C-x*-C
FT   DISULFID        218..247
FT   Condition: C-x*-C
FT   DISULFID        228..239
FT   Condition: C-x*-C
FT   DISULFID        296..331
FT   Condition: C-x*-C
FT   DISULFID        378..445
FT   Condition: C-x*-C
FT   DISULFID        385..418
FT   Condition: C-x*-C
FT   DISULFID        598..604
FT   Condition: C-x*-C
XX
Size: 832-876;
Related: None;
Template: P04578;
Scope:
 Viruses; Lentivirus
Fusion:
 Nter: None
 Cter: None
Duplicate: None
Plasmid: None
Comments: None
XX
# Revision 1.13 2023/12/15
//