P05923 (VPU_HV1BR) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein Vpu

Alternative name(s):
U ORF protein
Viral protein U

Gene names

Name:

vpu

Organism

Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI) (HIV-1) [Complete proteome]

Taxonomic identifier

11686 [NCBI]

Taxonomic lineage

Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group › Human immunodeficiency virus 1 › HIV-1 unknown group

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	81 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Enhances virion budding, by targeting human CD4 and Tetherin/BST2 to proteasome degradation. Degradation of CD4 prevents any unwanted premature interactions between viral Env and its receptor human CD4 in the endoplasmic reticulum. Degradation of antiretroviral protein Tetherin/BST2 is important for virion budding, as BST2 tethers new viral particles to the host cell membrane. Mechanistically, Vpu bridges either CD4 or BST2 to BTRC, a substrate recognition subunit of the Skp1/Cullin/F-box protein E3 ubiquitin ligase, induces their ubiquitination and subsequent proteasomal degradation. The alteration of the E3 ligase specificity by Vpu seems to interfere with the degradation of host IKBKB, leading to NF-kappa-B down-regulation and subsequent apoptosis. Ion channel activity has also been suggested, however, formation of cation-selective channel has been reconstituted ex-vivo in lipid bilayers. It is thus unsure that this activity plays a role in vivo By similarity. Ref.5 Ref.8 Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16 Ref.17
Enzyme regulation	Ion channel activity is inhibited by hexamethylene amiloride in vitro.
Subunit structure	May form pentamers or hexamers. Forms ternary complexes, by interacting with human CD4 and BTRC, and with human BST2 and BTRC By similarity.
Subcellular location	Host membrane; Single-pass type I membrane protein.
Domain	The N-terminal and transmembrane domains are required for proper virion budding, whereas the cytoplasmic domain is required for CD4 degradation. The cytoplasmic domain is composed of 2 amphipathic alpha helix By similarity. Ref.6
Post-translational modification	Phosphorylated by host CK2. This phosphorylation is necessary for interaction with human BTRC and degradation of CD4. Ref.3
Miscellaneous	The infectious clone pNL4-3 is a chimeric provirus that consists of DNA from HIV isolates NY5 (5' half) and BRU (3' half). 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).
Sequence similarities	Belongs to the HIV-1 VPU protein family.

Ontologies

Keywords
Biological process	Apoptosis 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 Ion transport Transport Viral immunoevasion
Cellular component	Host membrane Membrane
Disease	AIDS
Domain	Transmembrane Transmembrane helix
Molecular function	Ion channel
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological_process	RNA-dependent DNA replication Traceable author statement. Source: Reactome apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW entry into host cell Traceable author statement. Source: Reactome receptor catabolic process Inferred from electronic annotation. Source: InterPro 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 uncoating of virus Traceable author statement. Source: Reactome viral release from host cell Inferred from electronic annotation. Source: InterPro
Cellular_component	cytosol Traceable author statement. Source: Reactome endoplasmic reticulum membrane Traceable author statement. Source: Reactome host cell membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	cation channel 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
	Chain	1 – 81	81	Protein Vpu		PRO_0000085417
Regions
	Topological domain	1 – 7	7	Extracellular Potential
	Transmembrane	8 – 25	18	Helical; Potential
	Topological domain	26 – 81	56	Cytoplasmic Potential
Amino acid modifications
	Modified residue	52	1	Phosphoserine; by host CK2
	Modified residue	56	1	Phosphoserine; by host CK2
Natural variations
	Natural variant	5 – 6	2	QI → IV in strain: Clone pNL4-3.
	Natural variant	9	1	A → V in strain: Clone pNL4-3.
	Natural variant	60	1	I → V in strain: Clone pNL4-3.
Experimental info
	Mutagenesis	52	1	S → N: Complete loss of interaction with human BTRC, and of CD4 degradation activity; when associated with N-56. Ref.7
	Mutagenesis	56	1	S → N: Complete loss of interaction with human BTRC, and of CD4 degradation activity; when associated with N-52. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	P05923 [UniParc]. Last modified November 1, 1988. Version 1. Checksum: B9F588F7C6654B51	FASTA	81	9,160
	10 20 30 40 50 60 MQPIQIAIAA LVVAIIIAIV VWSIVIIEYR KILRQRKIDR LIDRLIERAE DSGNESEGEI 70 80 SALVEMGVEM GHHAPWDIDD L

References

[1]	"Nucleotide sequence of the AIDS virus, LAV." Wain-Hobson S., Sonigo P., Danos O., Cole S., Alizon M. Cell 40:9-17(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	Buckler C.E., Buckler-White A.J., Willey R.L., McCoy J. Submitted (JUN-1988) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA]. Strain: Clone pNL4-3.
[3]	"Human-immunodeficiency-virus-type-1-encoded Vpu protein is phosphorylated by casein kinase II." Schubert U., Schneider T., Henklein P., Hoffmann K., Berthold E., Hauser H., Pauli G., Porstmann T. Eur. J. Biochem. 204:875-883(1992) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION.
[4]	"The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: implications for the mechanism of degradation." Bour S., Schubert U., Strebel K. J. Virol. 69:1510-1520(1995) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HOST CD4.
[5]	"Identification of an ion channel activity of the Vpu transmembrane domain and its involvement in the regulation of virus release from HIV-1-infected cells." Schubert U., Ferrer-Montiel A.V., Oblatt-Montal M., Henklein P., Strebel K., Montal M. FEBS Lett. 398:12-18(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"The two biological activities of human immunodeficiency virus type 1 Vpu protein involve two separable structural domains." Schubert U., Bour S., Ferrer-Montiel A.V., Montal M., Maldarell F., Strebel K. J. Virol. 70:809-819(1996) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAINS.
[7]	"A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif." Margottin F., Bour S.P., Durand H., Selig L., Benichou S., Richard V., Thomas D., Strebel K., Benarous R. Mol. Cell 1:565-574(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HOST BTRCP, MUTAGENESIS OF SER-52 AND SER-56.
[8]	"The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor kappaB-dependent expression of antiapoptotic factors." Akari H., Bour S., Kao S., Adachi A., Strebel K. J. Exp. Med. 194:1299-1311(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN APOPTOSIS.
[9]	"Viral protein U counteracts a human host cell restriction that inhibits HIV-1 particle production." Varthakavi V., Smith R.M., Bour S.P., Strebel K., Spearman P. Proc. Natl. Acad. Sci. U.S.A. 100:15154-15159(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"The HIV-1 Vpu protein: a multifunctional enhancer of viral particle release." Bour S., Strebel K. Microbes Infect. 5:1029-1039(2003) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[11]	"Vpu and Tsg101 regulate intracellular targeting of the human immunodeficiency virus type 1 core protein precursor Pr55gag." Harila K., Prior I., Sjoberg M., Salminen A., Hinkula J., Suomalainen M. J. Virol. 80:3765-3772(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[12]	"HIV-1 Vpu promotes release and prevents endocytosis of nascent retrovirus particles from the plasma membrane." Neil S.J., Eastman S.W., Jouvenet N., Bieniasz P.D. PLoS Pathog. 2:354-367(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Drug-protein interaction with Vpu from HIV-1: proposing binding sites for amiloride and one of its derivatives." Kim C.G., Lemaitre V., Watts A., Fischer W.B. Anal. Bioanal. Chem. 386:2213-2217(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INHIBITION BY HEXAMETHYLENE AMILORIDE.
[14]	"The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein." Van Damme N., Goff D., Katsura C., Jorgenson R.L., Mitchell R., Johnson M.C., Stephens E.B., Guatelli J. Cell Host Microbe 3:245-252(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu." Neil S.J., Zang T., Bieniasz P.D. Nature 451:425-430(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[16]	"HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor." Goffinet C., Allespach I., Homann S., Tervo H.M., Habermann A., Rupp D., Oberbremer L., Kern C., Tibroni N., Welsch S., Krijnse-Locker J., Banting G., Krausslich H.G., Fackler O.T., Keppler O.T. Cell Host Microbe 5:285-297(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[17]	"Vpu directs the degradation of the human immunodeficiency virus restriction factor BST2/Tetherin via a {beta}TrCP-dependent mechanism." Douglas J.L., Viswanathan K., McCarroll M.N., Gustin J.K., Fruh K., Moses A.V. J. Virol. 83:7931-7947(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HOST BST2.

Cross-references

Sequence databases
EMBL GenBank DDBJ	K02013 Genomic RNA. Translation: AAB59750.1. M19921 Genomic RNA. Translation: AAA44991.1.
3D structure databases
ProteinModelPortal	P05923.
SMR	P05923. Positions 37-81.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Enzyme and pathway databases
Reactome	REACT_116125. Disease.
Family and domain databases
Gene3D	1.10.195.10. 1 hit.
InterPro	IPR008187. Vpu. IPR009032. Vpu_cyt. [Graphical view]
Pfam	PF00558. Vpu. 1 hit. [Graphical view]
SUPFAM	SSF57647. Vpu_cyt. 1 hit.
ProtoNet	Search...

Entry information

Entry name

VPU_HV1BR

Accession

Primary (citable) accession number: P05923

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1988
Last sequence update:	November 1, 1988
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