VPU - Viral Protein U

HIV VPU acts in the degradation of CD4 in the endoplasmic reticulum and the enhancement of virion release from the plasma membrane.



PDB-1VPU: HIV-1 (isolate SF_162) Vpu cytoplasmic domain fragment (residues 39-81) with R37L and K38Q mutations - produced using SwissModel/SPDBV/POVray

Key web links:
ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB: 1VPU (HIV-1 Vpu)
UniProt: P05919 (HIV-1 HXB2 Vpu)
Chime Tutorial:  not available
HIV-1/Human Protein Interaction DB: HIV-1 Vpu
Los Alamos HIV structure DB: not available
EMBL: K03455 [EMBL/GenBank/DDBJ]


Isoforms:

  • p16 (81 amino acids)

Function:

  • Vpu plays a role in HIV-induced CD4 downregulation by mediating the proteasomal degradation of newly synthesized CD4.
  • Vpu binds to CD4 at the endoplasmic reticulum (ER) membrane and recruits the SCF β-TrCP E3 ubiquitin ligase complex by directly interacting with β-TrCP.
  • This ubiquitination event targets CD4 degradation by the cytosolic proteasome through a dislocation step of CD4 which is mediated by the p97-UFD1L-NPL4 complex .
  • Vpu promotes progeny virion release from infected cells by antagonizing the tethering effect of BST2/tetherin .
  • Vpu also induces downregulation of the coactivating NK cell receptor NK, T-cell, B-cell antigen (NTB-A), as well as the activating NK cell receptor PVR/CD155 .

Localization:

  • Host cytoplasm
  • Host cell membrane
  • Virion

Additional Information:

  • Late timing of expression.
  • Vpu is unique to HIV-1/SIVcpz viruses.
  • The formation of Env-CD4 complexes interferes with virion assembly.
  • CD4 downregulation and increased virion release are genetically distinct; are related to different domains .

Vpu Function & Host-Virus Protein Interactions:[TOP]




Interactions highlighted in the image:


Potential interactions (not in the image):


  • Casein kinase II phosphorylation at positions Ser52 and Ser56.
  • Vpu binds a cellular protein UBP, which helps facilitate virus particle assembly and release.
  • There is either a direct interaction between Vpu and Gag, or an indirect interaction through UBP.
  • Vpu and AP1M1 interaction allows Vpu to hijack the AP-dependent trafficking pathways [see GUAVAh AP1M1 interaction profile].


Genomic Location & Protein Sequence: [TOP]

HIV-1 (HXB2):

          10         20         30         40         50         60         70         80
| | | | | | | |
QPIPIVAIVA LVVAIIIAIV VWSIVIIEYR KILRQRKIDR LIDRLIERAE DSGNESEGEI SALVEMGVEM GHHAPWDVDD L
[download in fasta format]

Length: 81 amino acids
Molecular Weight: 9111 Da
Theoretical pI: 4.69
Gene Description: Vpu translation initiation codon is not efficient .


Protein Domains/Folds/Motifs: [TOP]

InterPro:

VPU Protein - IPR008187



VPU Protein (C-terminal cytoplasmic domain) - IPR009032

  • is responsible for direct interaction with and degradation of the CD4 receptor.
  • encompasses the C-terminal half of the protein.
  • contains a few helical turns.
  • does not contain an apparent hydrophobic core.

Secondary Structure prediction:

Transmembrane Regions - tmhmm:


Low Complexity Regions - seg:


Antigenic Sites - EMBOSS:

Predicted Motifs: Printer-friendly version

N-glycosylation:
N-myristoylation:
Amidation:
Protein kinase C:
Casein kinase II:
Tyrosine kinase:
cAMP / cGMP kinase:
Cell attachment motif:
Asp Protease motif:
Asp Prot Retro motif:
Arginine-rich Region:
Isoleucine-rich Region:
Cysteine-rich Region:
Tryptophan-rich Region:
Zinc-finger CCHC motif:
Leucine Zipper motif:

Primary and Secondary Database Entries: [TOP]

Identifiers:



ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB/MMDB: Search for HIV-1 & VPU

UniProt: P05919 (HIV-1 HXB2 Vpu)
EMBL: K03455; CDS Not Annotated [EMBL/GenBank/DDBJ]

InterPro: IPR008187 Vpu / IPR009032 Vpu_cyt
Pfam: PF00558
Prints: none
SCOP: SSF57647 HIV-1 VPU cytoplasmic domain
BLOCKS: P05919
Prosite: P05919
ProtoNet: P05919
Database of Interacting Proteins: P05919
ModBase: P05919
HIV-1/Human Protein Interaction DB: HIV-1 Vpu
HIV-1 Sequence Database Los Alamos HIV Sequence Database

PDB:




Reviews and References: [TOP]

1 - HIV Sequence Compendium 2000
Kuiken CL, Foley B, Hahn B, Korber B, Marx PA, McCutchan F, Mellors JW, Mullins JI, Sodroski J, Wolinksy S.
Theoretical Biol. & Biophys. Group, Los Alamos Nat Lab, LA-UR 01-3860 [Read it online: Compendium]
2 - Retroviruses
Coffin JM, Hughes SH, Varmus HE.
CD-ROM ed. (2002) Cold Spring Harbor Laboratory Press [Read it online: NCBI Bookshelf]
3 - Identification and localization of vpr gene product of human immunodeficiency virus type 1.
Sato A, Igarashi H, Adachi A.
Virus Genes 4: 303-312 (1990) [pubmed: 2149621]
4 - Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple
bicistronic mRNAs.
Schwartz S, Felber BK, Fenyo EM, Pavlakis GN.
J Virol 64: 5448-5456 (1990) [pubmed: 2214021]
5 - The two biological activities of human immunodeficiency virus type 1 Vpu protein involve
two separable structural domains.
Schubert U, Bour S, Ferrer-Montiel AV.
J Virol 70: 809-819 (1996) [pubmed: 8551619]
6 - Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4.
Willey RL, Maldarelli F, Martin MA.
J Virol 66(12): 7193-7200 (1992) [pubmed: 1433512]
7 - The human immunodeficiency virus type 1-specific protein vpu is required for efficient virus
maturation and release.
Klimkait T, Strebel K, Hoggan MD.
J Virol 64: 621-629 (1990) [pubmed: 2404139]
8 - Modulation of HIV-1-host interaction: role of the Vpu accessory protein.
Dubé M, Bego MG, Paquay C, Cohen ÉA.
Retrovirology 7:114 (2010) [pubmed: 21176220]
9 - HIV-1 Vpu affects the anterograde transport and the glycosylation pattern of NTB-A.
Bolduan S, Hubel P, Reif T, Lodermeyer V, Höhne K, Fritz JV, Sauter D, Kirchhoff F, Fackler OT, Schindler M, Schubert U.
Virology 440(2):190-203 (2013) [pubmed: 23528733]
10 - HIV-1 Vpu mediated downregulation of CD155 requires alanine residues 10, 14 and 18 of the transmembrane domain.
Bolduan S, Reif T, Schindler M, Schubert U.
Virology 464-465:375-84 (2014) [pubmed: 25113908]
11 - Mapping the interaction between the cytoplasmic domains of HIV-1 viral protein U and human CD4 with NMR spectroscopy.
Singh SK, Möckel L, Thiagarajan-Rosenkranz P, Wittlich M, Willbold D, Koenig BW.
FEBS J. 279(19):3705-14 (2012) [pubmed: 22863293]
12 - 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 SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K, Benarous R.
Mol Cell 1(4):565-74 (1998) [pubmed: 9660940]
13 - HIV-1 Vpu protein antagonizes innate restriction factor BST-2 via lipid-embedded helix-helix interactions.
Skasko M, Wang Y, Tian Y, Tokarev A, Munguia J, Ruiz A, Stephens EB, Opella SJ, Guatelli J.
J Biol Chem. 287(1):58-67 (2012) [pubmed: 22072710]
14 - Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1.
Jia X, Weber E, Tokarev A, Lewinski M, Rizk M, Suarez M, Guatelli J, Xiong Y.
Elife 3:e02362 (2014) [pubmed: 24843023]



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