P04577 (ENV_HV2RO) 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 A (isolate ROD) (HIV-2) [Complete proteome]

Taxonomic identifier

11720 [NCBI]

Taxonomic lineage

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

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	858 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

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. Ref.2
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 – 19	19	Potential
	Chain	20 – 858	839	Envelope glycoprotein gp160		PRO_0000239503
	Chain	20 – 511	492	Surface protein gp120 By similarity		PRO_0000038449
	Chain	512 – 858	347	Transmembrane protein gp41 By similarity		PRO_0000038450
Regions
	Topological domain	20 – 679	660	Extracellular Potential
	Transmembrane	680 – 700	21	Helical; Potential
	Topological domain	701 – 858	158	Cytoplasmic Potential
	Region	110 – 162	53	V1
	Region	163 – 205	43	V2
	Region	305 – 339	35	V3
	Region	399 – 419	21	V4
	Region	462 – 469	8	V5
	Region	512 – 532	21	Fusion peptide Potential
	Region	575 – 591	17	Immunosuppression By similarity
	Region	657 – 678	22	MPER; binding to GalCer By similarity
	Coiled coil	624 – 645	22	Potential
	Motif	707 – 710	4	YXXV motif; contains endocytosis signal By similarity
	Motif	857 – 858	2	Di-leucine internalization motif By similarity
Sites
	Site	?511 – ?512	2	Cleavage; by host furin Potential
Amino acid modifications
	Lipidation	773	1	S-palmitoyl cysteine; by host By similarity
	Glycosylation	34	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	67	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	76	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	119	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	120	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	151	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	166	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	179	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	192	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	193	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	196	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	206	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	238	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	241	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	248	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	272	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	278	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	289	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	300	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	310	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	367	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	371	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	400	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	410	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	447	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	463	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	466	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	611	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	620	1	N-linked (GlcNAc...); by host Potential
	Glycosylation	636	1	N-linked (GlcNAc...); by host Potential
	Disulfide bond	41 ↔ 54		By similarity
	Disulfide bond	98 ↔ 214		By similarity
	Disulfide bond	105 ↔ 205		By similarity
	Disulfide bond	110 ↔ 163		By similarity
	Disulfide bond	227 ↔ 257		By similarity
	Disulfide bond	237 ↔ 249		By similarity
	Disulfide bond	305 ↔ 340		By similarity
	Disulfide bond	392 ↔ 446		By similarity
	Disulfide bond	399 ↔ 419		By similarity
Experimental info
	Sequence conflict	312	1	T → I in AAB00770. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P04577 [UniParc]. Last modified August 13, 1987. Version 1. Checksum: C7266AF1F5C5B9A7	FASTA	858	98,824
	10 20 30 40 50 60 MMNQLLIAIL LASACLVYCT QYVTVFYGVP TWKNATIPLF CATRNRDTWG TIQCLPDNDD 70 80 90 100 110 120 YQEITLNVTE AFDAWNNTVT EQAIEDVWHL FETSIKPCVK LTPLCVAMKC SSTESSTGNN 130 140 150 160 170 180 TTSKSTSTTT TTPTDQEQEI SEDTPCARAD NCSGLGEEET INCQFNMTGL ERDKKKQYNE 190 200 210 220 230 240 TWYSKDVVCE TNNSTNQTQC YMNHCNTSVI TESCDKHYWD AIRFRYCAPP GYALLRCNDT 250 260 270 280 290 300 NYSGFAPNCS KVVASTCTRM METQTSTWFG FNGTRAENRT YIYWHGRDNR TIISLNKYYN 310 320 330 340 350 360 LSLHCKRPGN KTVKQIMLMS GHVFHSHYQP INKRPRQAWC WFKGKWKDAM QEVKETLAKH 370 380 390 400 410 420 PRYRGTNDTR NISFAAPGKG SDPEVAYMWT NCRGEFLYCN MTWFLNWIEN KTHRNYAPCH 430 440 450 460 470 480 IKQIINTWHK VGRNVYLPPR EGELSCNSTV TSIIANIDWQ NNNQTNITFS AEVAELYRLE 490 500 510 520 530 540 LGDYKLVEIT PIGFAPTKEK RYSSAHGRHT RGVFVLGFLG FLATAGSAMG AASLTVSAQS 550 560 570 580 590 600 RTLLAGIVQQ QQQLLDVVKR QQELLRLTVW GTKNLQARVT AIEKYLQDQA RLNSWGCAFR 610 620 630 640 650 660 QVCHTTVPWV NDSLAPDWDN MTWQEWEKQV RYLEANISKS LEQAQIQQEK NMYELQKLNS 670 680 690 700 710 720 WDIFGNWFDL TSWVKYIQYG VLIIVAVIAL RIVIYVVQML SRLRKGYRPV FSSPPGYIQQ 730 740 750 760 770 780 IHIHKDRGQP ANEETEEDGG SNGGDRYWPW PIAYIHFLIR QLIRLLTRLY SICRDLLSRS 790 800 810 820 830 840 FLTLQLIYQN LRDWLRLRTA FLQYGCEWIQ EAFQAAARAT RETLAGACRG LWRVLERIGR 850 GILAVPRRIR QGAEIALL

References

[1]	"Genome organization and transactivation of the human immunodeficiency virus type 2." Guyader M., Emerman M., Sonigo P., Clavel F., Montagnier L., Alizon M. Nature 326:662-669(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"DC-SIGN interactions with human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus." Pohlmann S., Baribaud F., Lee B., Leslie G.J., Sanchez M.D., Hiebenthal-Millow K., Munch J., Kirchhoff F., Doms R.W. J. Virol. 75:4664-4672(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION OF SURFACE PROTEIN GP120 WITH HOST CD209/DC-SIGN. Strain: Isolate rod10.
[3]	"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	M15390 Genomic DNA. Translation: AAB00770.1. X05291 Genomic RNA. Translation: CAA28914.1.
PIR	VCLJG2. C26262.
3D structure databases
ProteinModelPortal	P04577.
SMR	P04577. Positions 61-487, 538-660.
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_HV2RO

Accession

Primary (citable) accession number: P04577

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	August 13, 1987
Last modified:	April 3, 2013
This is version 92 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program