Q76638 (ENV_HV2UC) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Envelope glycoprotein gp160

Alternative name(s):
Env polyprotein

Cleaved into the following 2 chains:

1. Surface protein gp120
   Short name=SU
   Alternative name(s):
   Glycoprotein 120
   Short name=gp120
2. Transmembrane protein gp41
   Short name=TM
   Alternative name(s):
   Glycoprotein 41
   Short name=gp41

Gene names

Name:

env

Organism

Human immunodeficiency virus type 2 subtype B (isolate UC1) (HIV-2) [Complete proteome]

Taxonomic identifier

388822 [NCBI]

Taxonomic lineage

Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group › Human immunodeficiency virus 2 › HIV-2 subtype B

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	857 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Inferred from homology

General annotation (Comments)

Function	The surface protein gp120 (SU) 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. This peculiar 2 stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. Since CD4 also displays a binding site for the disulfide-isomerase P4HB/PDI, a P4HB/PDI-CD4-CXCR4-gp120 complex may form. In that complex, P4HB/PDI could reach and reduce gp120 disulfide bonds, causing major conformational changes in gp120. TXN, another PDI family member could also be involved in disulfide rearrangements in Env during fusion. These changes are transmitted to the transmembrane protein gp41 and are thought to activate its fusogenic potential by unmasking its fusion peptide By similarity. The surface protein gp120 is 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. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they take up antigen, process it, and present it to T-cells following migration to lymphoid organs. 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. Virion capture also seems to lead to MHC-II-restricted viral antigen presentation, and probably to the activation of HIV-specific CD4+ cells By similarity. The transmembrane protein gp41 (TM) 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 By similarity. The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface By similarity. The gp120-gp41 heterodimer seems to contribute to T-cell depletion during HIV-1 infection. The envelope glycoproteins expressed on the surface of infected cells induce apoptosis through an interaction with uninfected cells expressing the receptor (CD4) and the coreceptors CXCR4 or CCR5. This type of bystander killing may be obtained by at least three distinct mechanisms. First, the interaction between the 2 cells can induce cellular fusion followed by nuclear fusion within the syncytium. Syncytia are condemned to die from apoptosis. Second, the 2 interacting cells may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. Third, it is possible that virus-infected cells, on the point of undergoing apoptosis, fuse with CD4-expressing cells, in which case apoptosis is rapidly transmitted from one cell to the other and thus occurs in a sort of contagious fashion By similarity. The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves By similarity.
Subunit structure	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 human CD4, CCR5 and CXCR4, to form a P4HB/PDI-CD4-CXCR4-gp120 complex. 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 By similarity.
Subcellular location	Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein By similarity. Host cell membrane; Single-pass type I membrane protein By similarity. Host endosome membrane; Single-pass type I membrane protein Potential. 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 By similarity. Surface protein gp120: Virion membrane; Peripheral membrane protein By similarity. Host cell membrane; Peripheral membrane protein By similarity. Host endosome membrane; Peripheral membrane protein Potential. 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 By similarity.
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. Binding to CCR5 involves a region adjacent in addition to V3 By similarity. 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 By similarity.
Post-translational modification	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 By similarity. 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 By similarity.
Miscellaneous	Some HIV-2 isolates have been described that can infect cells independently of CD4, using CXCR4 as primary receptor. These isolates may have an exposed coreceptor binding site.

Ontologies

Keywords
Biological process	Apoptosis 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 Inhibition of host innate immune response by virus Inhibition of host interferon signaling pathway by virus Inhibition of host tetherin by virus Viral attachment to host cell Viral immunoevasion Viral penetration into host cytoplasm Virus endocytosis by host Virus entry into host cell
Cellular component	Host cell membrane Host endosome Host membrane Membrane Viral envelope protein Virion
Disease	AIDS
Domain	Coiled coil Signal Transmembrane Transmembrane helix
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein Lipoprotein Palmitate
Technical term	Complete proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host tetherin activity Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host type I interferon-mediated signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW viral attachment to host cell Inferred from electronic annotation. Source: UniProtKB-KW viral entry into host cell via clathrin-mediated endocytosis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	host cell endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell host cell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW viral envelope Inferred from electronic annotation. Source: UniProtKB-KW virion membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	structural molecule activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 26	26	Potential
	Chain	27 – 857	831	Envelope glycoprotein gp160 By similarity		PRO_0000244705
	Chain	27 – 514	488	Surface protein gp120 By similarity		PRO_0000244706
	Chain	515 – 857	343	Transmembrane protein gp41 By similarity		PRO_0000244707
Regions
	Topological domain	27 – 682	656	Extracellular Potential
	Transmembrane	683 – 703	21	Helical; Potential
	Topological domain	704 – 857	154	Cytoplasmic Potential
	Region	115 – 163	49	V1
	Region	164 – 204	41	V2
	Region	304 – 336	33	V3
	Region	396 – 419	24	V4
	Region	464 – 472	9	V5
	Region	515 – 535	21	Fusion peptide Potential
	Region	578 – 594	17	Immunosuppression By similarity
	Region	660 – 681	22	MPER; binding to GalCer By similarity
	Coiled coil	627 – 648	22	Potential
	Motif	710 – 713	4	YXXV motif; contains endocytosis signal By similarity
	Motif	856 – 857	2	Di-leucine internalization motif By similarity
	Compositional bias	552 – 556	5	Poly-Gln
Sites
	Site	514 – 515	2	Cleavage; by host furin By similarity
Amino acid modifications
	Lipidation	776	1	S-palmitoyl cysteine; by host By similarity
	Glycosylation	39	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	72	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	81	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	116	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	121	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	142	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	150	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	167	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	193	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	205	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	237	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	240	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	271	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	277	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	288	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	299	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	309	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	364	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	397	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	407	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	447	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	464	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	469	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	614	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	623	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	639	1	N-linked (GlcNAc...); by host Potential
	Disulfide bond	46 ↔ 59		By similarity
	Disulfide bond	103 ↔ 213		By similarity
	Disulfide bond	110 ↔ 204		By similarity
	Disulfide bond	115 ↔ 164		By similarity
	Disulfide bond	226 ↔ 256		By similarity
	Disulfide bond	236 ↔ 248		By similarity
	Disulfide bond	304 ↔ 337		By similarity
	Disulfide bond	389 ↔ 446		By similarity
	Disulfide bond	396 ↔ 419		By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q76638 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 26411B789A4A1482	FASTA	857	98,643
	10 20 30 40 50 60 MAHTSNHLFI LLLLISVYGF LGHKKNYVTV FYGIPAWRNA TVPLFCATTN RDTWGTVQCL 70 80 90 100 110 120 PDNGDYTEIS VNITEAFDAW NNTVTEQAVD DVWSLFETSI KPCVKLTPLC VAMRCNNTGT 130 140 150 160 170 180 NTTTKPITTP ITTTKPSENL LNDTSPCIKN DTCPGIGLEN TVDCYFNMTG LRRDEKKQYK 190 200 210 220 230 240 DTWYEKDLEC NGNSTSTICY MRTCNTSVIQ ESCDKHYWDS LRFRYCAPPG YALLRCNDTN 250 260 270 280 290 300 YSGFMPKCSK VVVSSCTRMM ETQTSTWFGF NGTRTENRTY MYWHSKDNRT IISLNKYYNL 310 320 330 340 350 360 TMHCRRPGNK TVIPITIMSG LNFHSQPLNT RPRQAWCWFK GNWIEAIREV KETIIKHPRY 370 380 390 400 410 420 KGTNNTERIR LVGPSAGSDP EVRHMWTNCR GEFFYCNMTW FLNWVENRTG TTQKNYVTCH 430 440 450 460 470 480 IKQIVNTWHK VGKYVYLPPR EGTLSCNSSV TSLIANIDVY YDGNDTKTNI TMSAEVGELY 490 500 510 520 530 540 RLELGDYKLV EITPIGFAPT EIKRYSSTTP RNKRGVMVLG FLGLLAMAGS AMGATSLTLS 550 560 570 580 590 600 AQSRTLLAGI VQQQQQLLDV VKRQQELLRL TVWGTKNLQT RVTAIEKYLK DQALLNSWGC 610 620 630 640 650 660 AFRQVCHTTV PWPNETLTPD WENMTWQQWE KRVNFLDANI TALLEEAQIQ QERNMYELQK 670 680 690 700 710 720 LNSWDVFGNW FDFTSWMAYI RLGLYVVAGL IVLRIVIYIM QMLARLRKGY RPVFSSPPSY 730 740 750 760 770 780 TQQIPIRKHR GQPANEETED EGGNEGAYRS WPWQIEYAHF LIRQLRNLLI WLYNGCRNLL 790 800 810 820 830 840 LKTSQILQPA LQPLRLSLAY LQYGISWFQE AIQAATRAAR ETLANTGRAL WKALRRTAEA 850 IIAIPRRIRQ GLELALL

References

[1]	"Distinguishing features of an infectious molecular clone of the highly divergent and noncytopathic human immunodeficiency virus type 2 UC1 strain." Barnett S.W., Quiroga M., Werner A., Dina D., Levy J.A. J. Virol. 67:1006-1014(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Human immunodeficiency virus type 2." Reeves J.D., Doms R.W. J. Gen. Virol. 83:1253-1265(2002) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L07625 Genomic RNA. Translation: AAA43946.1.
PIR	A45713.
3D structure databases
ProteinModelPortal	Q76638.
SMR	Q76638. Positions 66-490, 541-663.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Family and domain databases
Gene3D	2.170.40.20. 2 hits.
InterPro	IPR000777. HIV1_GP160. IPR000328. Retroviral_envelope_protein. [Graphical view]
Pfam	PF00516. GP120. 1 hit. PF00517. GP41. 1 hit. [Graphical view]
SUPFAM	SSF56502. GP120. 1 hit.
ProtoNet	Search...

Entry information

Entry name

ENV_HV2UC

Accession

Primary (citable) accession number: Q76638

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 27, 2006
Last sequence update:	November 1, 1996
Last modified:	April 3, 2013
This is version 86 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program