VPU_HV1H2
ID VPU_HV1H2 Reviewed; 81 AA.
AC P05919;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1988, sequence version 1.
DT 29-SEP-2021, entry version 133.
DE RecName: Full=Protein Vpu {ECO:0000255|HAMAP-Rule:MF_04082};
DE AltName: Full=U ORF protein {ECO:0000255|HAMAP-Rule:MF_04082};
DE AltName: Full=Viral protein U {ECO:0000255|HAMAP-Rule:MF_04082};
GN Name=vpu {ECO:0000255|HAMAP-Rule:MF_04082};
OS Human immunodeficiency virus type 1 group M subtype B (isolate HXB2)
OS (HIV-1).
OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes;
OC Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus.
OX NCBI_TaxID=11706;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=3040055; DOI=10.1089/aid.1987.3.57;
RA Ratner L., Fisher A., Jagodzinski L.L., Mitsuya H., Liou R.-S., Gallo R.C.,
RA Wong-Staal F.;
RT "Complete nucleotide sequences of functional clones of the AIDS virus.";
RL AIDS Res. Hum. Retroviruses 3:57-69(1987).
RN [2]
RP TOPOLOGY, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=8331740; DOI=10.1128/jvi.67.8.5056-5061.1993;
RA Maldarelli F., Chen M.Y., Willey R.L., Strebel K.;
RT "Human immunodeficiency virus type 1 Vpu protein is an oligomeric type I
RT integral membrane protein.";
RL J. Virol. 67:5056-5061(1993).
RN [3]
RP PHOSPHORYLATION AT SER-52 AND SER-56.
RX PubMed=8107101; DOI=10.1006/jmbi.1994.1114;
RA Schubert U., Henklein P., Boldyreff B., Wingender E., Strebel K.,
RA Porstmann T.;
RT "The human immunodeficiency virus type 1 encoded Vpu protein is
RT phosphorylated by casein kinase-2 (CK-2) at positions Ser52 and Ser56
RT within a predicted alpha-helix-turn-alpha-helix-motif.";
RL J. Mol. Biol. 236:16-25(1994).
RN [4]
RP INTERACTION WITH HOST CD4.
RX PubMed=7853484; DOI=10.1128/jvi.69.3.1510-1520.1995;
RA Bour S., Schubert U., Strebel K.;
RT "The human immunodeficiency virus type 1 Vpu protein specifically binds to
RT the cytoplasmic domain of CD4: implications for the mechanism of
RT degradation.";
RL J. Virol. 69:1510-1520(1995).
RN [5]
RP FUNCTION.
RX PubMed=8794357; DOI=10.1128/jvi.70.10.7108-7115.1996;
RA Ewart G.D., Sutherland T., Gage P.W., Cox G.B.;
RT "The Vpu protein of human immunodeficiency virus type 1 forms cation-
RT selective ion channels.";
RL J. Virol. 70:7108-7115(1996).
RN [6]
RP INTERACTION WITH HOST BTRC.
RX PubMed=9660940; DOI=10.1016/s1097-2765(00)80056-8;
RA Margottin F., Bour S.P., Durand H., Selig L., Benichou S., Richard V.,
RA Thomas D., Strebel K., Benarous R.;
RT "A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu
RT connects CD4 to the ER degradation pathway through an F-box motif.";
RL Mol. Cell 1:565-574(1998).
RN [7]
RP FUNCTION.
RX PubMed=11696595; DOI=10.1084/jem.194.9.1299;
RA Akari H., Bour S., Kao S., Adachi A., Strebel K.;
RT "The human immunodeficiency virus type 1 accessory protein Vpu induces
RT apoptosis by suppressing the nuclear factor kappaB-dependent expression of
RT antiapoptotic factors.";
RL J. Exp. Med. 194:1299-1311(2001).
RN [8]
RP FUNCTION, AND INTERACTION WITH HOST FBXW11.
RX PubMed=19730691; DOI=10.1371/journal.ppat.1000574;
RA Mangeat B., Gers-Huber G., Lehmann M., Zufferey M., Luban J., Piguet V.;
RT "HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it
RT and directing its beta-TrCP2-dependent degradation.";
RL PLoS Pathog. 5:E1000574-E1000574(2009).
RN [9]
RP FUNCTION, AND INTERACTION WITH HOST BST2.
RX PubMed=19837671; DOI=10.1074/jbc.m109.058305;
RA Iwabu Y., Fujita H., Kinomoto M., Kaneko K., Ishizaka Y., Tanaka Y.,
RA Sata T., Tokunaga K.;
RT "HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin
RT through transmembrane interactions leading to lysosomes.";
RL J. Biol. Chem. 284:35060-35072(2009).
RN [10]
RP SUBUNIT.
RX PubMed=24223193; DOI=10.1371/journal.pone.0079779;
RA Padhi S., Khan N., Jameel S., Priyakumar U.D.;
RT "Molecular dynamics simulations reveal the HIV-1 Vpu transmembrane protein
RT to form stable pentamers.";
RL PLoS ONE 8:E79779-E79779(2013).
RN [11]
RP REVIEW.
RX PubMed=24822052; DOI=10.3389/fmicb.2014.00177;
RA Roy N., Pacini G., Berlioz-Torrent C., Janvier K.;
RT "Mechanisms underlying HIV-1 Vpu-mediated viral egress.";
RL Front. Microbiol. 5:177-177(2014).
RN [12]
RP FUNCTION, AND INTERACTION WITH HOST AP1M1.
RX PubMed=24843023; DOI=10.7554/elife.02362;
RA Jia X., Weber E., Tokarev A., Lewinski M., Rizk M., Suarez M., Guatelli J.,
RA Xiong Y.;
RT "Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of
RT the clathrin adaptor protein complex 1.";
RL Elife 3:E02362-E02362(2014).
RN [13]
RP FUNCTION.
RX PubMed=24498878; DOI=10.1186/1742-4690-11-15;
RA Pham T.N., Lukhele S., Hajjar F., Routy J.P., Cohen E.A.;
RT "HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated
RT cell lysis through down-modulation of CD4 and BST2.";
RL Retrovirology 11:15-15(2014).
CC -!- FUNCTION: Enhances virion budding by targeting host CD4 and
CC Tetherin/BST2 to proteasome degradation. Degradation of CD4 prevents
CC any unwanted premature interactions between viral Env and its host
CC receptor CD4 in the endoplasmic reticulum. Degradation of
CC antiretroviral protein Tetherin/BST2 is important for virion budding,
CC as BST2 tethers new viral particles to the host cell membrane.
CC Mechanistically, Vpu bridges either CD4 or BST2 to BTRC, a substrate
CC recognition subunit of the Skp1/Cullin/F-box protein E3 ubiquitin
CC ligase, induces their ubiquitination and subsequent proteasomal
CC degradation. The alteration of the E3 ligase specificity by Vpu seems
CC to promote the degradation of host IKBKB, leading to NF-kappa-B down-
CC regulation and subsequent apoptosis. Ion channel activity has also been
CC suggested, however, formation of cation-selective channel has been
CC reconstituted ex-vivo in lipid bilayers. It is thus unsure that this
CC activity plays a role in vivo. {ECO:0000255|HAMAP-Rule:MF_04082,
CC ECO:0000269|PubMed:11696595, ECO:0000269|PubMed:19730691,
CC ECO:0000269|PubMed:19837671, ECO:0000269|PubMed:24498878,
CC ECO:0000269|PubMed:24843023, ECO:0000269|PubMed:8794357}.
CC -!- ACTIVITY REGULATION: Ion channel activity is inhibited by hexamethylene
CC amiloride in vitro. {ECO:0000255|HAMAP-Rule:MF_04082}.
CC -!- SUBUNIT: Forms pentamers or hexamers. Interacts with host CD4 and BRTC;
CC these interactions induce proteasomal degradation of CD4. Interacts
CC with host BST2; this interaction leads to the degradation of host BST2.
CC Interacts with host FBXW11. Interacts with host AP1M1; this interaction
CC plays a role in the mistrafficking and subsequent degradation of host
CC BST2. {ECO:0000255|HAMAP-Rule:MF_04082, ECO:0000269|PubMed:19730691,
CC ECO:0000269|PubMed:19837671, ECO:0000269|PubMed:24223193,
CC ECO:0000269|PubMed:24843023, ECO:0000269|PubMed:7853484,
CC ECO:0000269|PubMed:8331740, ECO:0000269|PubMed:9660940}.
CC -!- INTERACTION:
CC P05919; P01730: CD4; Xeno; NbExp=3; IntAct=EBI-6248147, EBI-353826;
CC -!- SUBCELLULAR LOCATION: Host membrane {ECO:0000255|HAMAP-Rule:MF_04082};
CC Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04082,
CC ECO:0000269|PubMed:8331740}.
CC -!- DOMAIN: The N-terminal and transmembrane domains are required for
CC proper virion budding, whereas the cytoplasmic domain is required for
CC CD4 degradation. The cytoplasmic domain is composed of 2 amphipathic
CC alpha helix. {ECO:0000255|HAMAP-Rule:MF_04082}.
CC -!- PTM: Phosphorylated by host CK2. This phosphorylation is necessary for
CC interaction with human BTRC and degradation of CD4. {ECO:0000255|HAMAP-
CC Rule:MF_04082}.
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 {ECO:0000255|HAMAP-Rule:MF_04082}.
CC -!- SIMILARITY: Belongs to the HIV-1 VPU protein family.
CC {ECO:0000255|HAMAP-Rule:MF_04082}.
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DR EMBL; K03455; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR PDB; 2N29; NMR; -; A=28-81.
DR PDBsum; 2N29; -.
DR BMRB; P05919; -.
DR SMR; P05919; -.
DR IntAct; P05919; 56.
DR TCDB; 1.A.40.1.1; the human immunodeficiency virus type i, hiv-1 (retrovirdiac) vpu channel (vpu-c) family.
DR iPTMnet; P05919; -.
DR PRIDE; P05919; -.
DR Reactome; R-HSA-162585; Uncoating of the HIV Virion.
DR Reactome; R-HSA-162588; Budding and maturation of HIV virion.
DR Reactome; R-HSA-162592; Integration of provirus.
DR Reactome; R-HSA-162594; Early Phase of HIV Life Cycle.
DR Reactome; R-HSA-164516; Minus-strand DNA synthesis.
DR Reactome; R-HSA-164525; Plus-strand DNA synthesis.
DR Reactome; R-HSA-164843; 2-LTR circle formation.
DR Reactome; R-HSA-171286; Synthesis and processing of ENV and VPU.
DR Reactome; R-HSA-173107; Binding and entry of HIV virion.
DR Reactome; R-HSA-175474; Assembly Of The HIV Virion.
DR Reactome; R-HSA-175567; Integration of viral DNA into host genomic DNA.
DR Reactome; R-HSA-177539; Autointegration results in viral DNA circles.
DR Reactome; R-HSA-180534; Vpu mediated degradation of CD4.
DR Reactome; R-HSA-180689; APOBEC3G mediated resistance to HIV-1 infection.
DR Reactome; R-HSA-180910; Vpr-mediated nuclear import of PICs.
DR Proteomes; UP000002241; Genome.
DR GO; GO:0033644; C:host cell membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-UniRule.
DR GO; GO:0005261; F:cation channel activity; IEA:UniProtKB-UniRule.
DR GO; GO:0042609; F:CD4 receptor binding; IEA:UniProtKB-UniRule.
DR GO; GO:0032801; P:receptor catabolic process; IEA:UniProtKB-UniRule.
DR GO; GO:0039587; P:suppression by virus of host tetherin activity; IEA:UniProtKB-UniRule.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-UniRule.
DR GO; GO:0019076; P:viral release from host cell; IEA:UniProtKB-UniRule.
DR Gene3D; 1.10.195.10; -; 1.
DR HAMAP; MF_04082; HIV_VPU; 1.
DR InterPro; IPR008187; Vpu.
DR InterPro; IPR009032; Vpu_cyt_dom_sf.
DR Pfam; PF00558; Vpu; 1.
DR SUPFAM; SSF57647; SSF57647; 1.
PE 1: Evidence at protein level;
KW 3D-structure; AIDS; Apoptosis; Host membrane; Host-virus interaction;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host tetherin by virus; Ion channel; Ion transport; Membrane;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix;
KW Transport; Viral immunoevasion.
FT CHAIN 1..81
FT /note="Protein Vpu"
FT /id="PRO_0000085433"
FT TOPO_DOM 1..6
FT /note="Extracellular"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082"
FT TRANSMEM 7..27
FT /note="Helical"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082"
FT TOPO_DOM 28..81
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082"
FT MOD_RES 52
FT /note="Phosphoserine; by host CK2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082,
FT ECO:0000269|PubMed:8107101"
FT MOD_RES 56
FT /note="Phosphoserine; by host CK2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082,
FT ECO:0000269|PubMed:8107101"
FT HELIX 36..40
FT /evidence="ECO:0007829|PDB:2N29"
FT HELIX 41..50
FT /evidence="ECO:0007829|PDB:2N29"
FT HELIX 57..69
FT /evidence="ECO:0007829|PDB:2N29"
FT TURN 73..76
FT /evidence="ECO:0007829|PDB:2N29"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:2N29"
SQ SEQUENCE 81 AA; 9111 MW; 53A951D6240556EA CRC64;
QPIPIVAIVA LVVAIIIAIV VWSIVIIEYR KILRQRKIDR LIDRLIERAE DSGNESEGEI
SALVEMGVEM GHHAPWDVDD L
