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8  structures 58  species 0  interactions 6152  sequences 3  architectures

Family: Vpu (PF00558)

Summary: Vpu protein

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Vpu Edit Wikipedia article

PDB 1pje EBI.jpg
structure of the channel-forming trans-membrane domain of virus protein "u" (vpu) from HIV-1
Symbol Vpu
Pfam PF00558
InterPro IPR008187
SCOP 1vpu
TCDB 1.A.40
Viral Protein Unique
Organism HIV-1
Symbol vpu
Entrez 155945
RefSeq (Prot) NP_057855.1
UniProt Q9WB91
Other data
Chromosome viral genome: 0.01 - 0.01 Mb

Vpu is a protein that in HIV is encoded by the vpu gene. Vpu stands for "Viral Protein Unique". The Vpu gene is found exclusively in HIV-1 and some HIV-1-related simian immunodeficiency virus (SIV) isolates, such as SIVcpz, SIVgsn, and SIVmon, but not in HIV-2 or the majority of SIV isolates.[1] Structural similarities between Vpu and another small viral protein, M2, encoded by influenza A virus were first noted soon after the discovery of Vpu. Since then, M2 has been shown to form cation-selective ion channels when expressed in Xenopus oocytes or mammalian cells and also when purified and reconstituted into planar lipid bilayers.[2]

The Vpu protein acts in the degradation of CD4 in the endoplasmic reticulum and in the enhancement of virion release from the plasma membrane of infected cells.[3] Vpu induces the degradation of the CD4 viral receptor and therefore participates in the general downregulation of CD4 expression during the course of HIV infection. Vpu-mediated CD4 degradation is thought to prevent CD4-Env binding in the endoplasmic reticulum in order to facilitate proper Env assembly into virions.[4] It is found in the membranes of infected cells, but not the virus particles themselves.


Vpu and Env are expressed from the same bicistronic mRNA in a Rev-dependent manner, presumably by leaky scanning of ribosomes through the vpu initiation codon.[5] In fact Vpu gene overlaps at its3′-end with the env gene. Several HIV-1 isolates were found to carry point mutations in the Vpu translation initiation codon but have otherwise intact vpu genes. Since removal of the Vpu initiation codon results in increased expression of the downstream env gene, it is possible that HIV-1 actually uses this mechanism as a molecular switch to regulate the relative expression of Vpu or Env in infected cells. The possible benefits of such a regulation are unclear.[6]


Two main functions have been assigned to the Vpu protein, the first one is known to induce degradation of the viral receptor molecule CD4 and to enhance the release of newly formed virions from the cell surface. Vpu accomplishes these two functions through two distinct mechanisms. In the case of CD4, Vpu acts as a molecular adaptor to connect CD4 to an E3 ubiquitin ligase complex resulting in CD4 degradation by cellular proteasomes. This requires signals located in Vpu’s cytoplasmic domain. Enhancement of virus release on the other hand involves the neutralization of a cellular host factor, BST-2 (also known as CD317, HM1.24, or tetherin) and requires Vpu’s TM domain.[7] however, the exact mechanism of how Vpu counteracts BST-2 is still unclear.[6] In the absence of Vpu, tetherin binds to the viral envelope and ties it to the cell membrane and other viral particles, impeding release of the viral particles. Recent data suggest that the BST-2 transmembrane domain is crucial for interference by Vpu. The interaction of Vpu and BST-2 results in the downregulation of BST-2 from the cell surface.[8]

BST-2, which is an interferon (IFN)-inducible cell surface protein, appears to “tether” HIV to the cell in the absence of Vpu. BST-2 is a heavily glycosylated 29- to 33-kDa integral membrane protein with both a transmembrane domain and a putative glycosylphosphatidylinositol anchor (GPI).[9] At the cell surface, BST2 resides in lipid rafts through the GPI anchor, whereas its TM domain lies outside them, indirectly interacting with the actin cytoskeleton. Vpu primary site of action is the plasma membrane, where this protein targets cell-surface BST-2 through their mutual TM-to-TM binding, leading to lysosomes, partially dependent on βTrCP.[10]


Virus protein "u" (Vpu) is an oligomeric, 81-amino acid type I membrane protein (16 kDa) that is translated from vpu-env bicistronic mRNA. The N-terminus of Vpu encoding the transmembrane (TM) anchor represents an active domain important for the regulation of virus release but not CD4 degradation.The C-terminal cytoplasmic domain (54 residues) that contains a pair of serine residues (at positions 52 and 56) constitutively phosphorylated by casein kinase II. The phosphorylation of two serine residues in the cytoplasmic domain is critical for CD4 degradation in the ER.[11] Based on 2D 1H NMR spectroscopy of a peptide corresponding to the cytoplasmic domain of Vpu, it was proposed that the cytoplasmic domain of Vpu contains two α-helical domains, helix-1 and helix-2, which are connected by an unstructured region containing the two conserved phosphoseryl residues. In addition, computer models predict a third α-helical domain in the transmembrane domain of Vpu, which could play an important role in the formation of ion channels.[12]

See also[edit]


  1. ^ Hussain A, Wesley C, Khalid M, Chaudhry A, Jameel S (January 2008). "Human immunodeficiency virus type 1 Vpu protein interacts with CD74 and modulates major histocompatibility complex class II presentation". Journal of Virology 82 (2): 893–902. doi:10.1128/JVI.01373-07. PMC 2224584. PMID 17959659. 
  2. ^ Ewart GD, Sutherland T, Gage PW, Cox GB (October 1996). "The Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels". Journal of Virology 70 (10): 7108–15. PMC 190763. PMID 8794357. 
  3. ^ Bour S, Schubert U, Strebel K (March 1995). "The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: implications for the mechanism of degradation". Journal of Virology 69 (3): 1510–20. PMC 188742. PMID 7853484. 
  4. ^ Estrabaud E, Le Rouzic E, Lopez-Vergès S, Morel M, Belaïdouni N, Benarous R, Transy C, Berlioz-Torrent C, Margottin-Goguet F (July 2007). "Regulated degradation of the HIV-1 Vpu protein through a betaTrCP-independent pathway limits the release of viral particles". PLoS Pathog. 3 (7): e104. doi:10.1371/journal.ppat.0030104. PMC 1933454. PMID 17676996. 
  5. ^ Göttlinger HG, Dorfman T, Cohen EA, Haseltine WA (August 1993). "Vpu protein of human immunodeficiency virus type 1 enhances the release of capsids produced by gag gene constructs of widely divergent retroviruses". Proc. Natl. Acad. Sci. U.S.A. 90 (15): 7381–5. PMC 47141. PMID 8346259. 
  6. ^ a b Strebel K (December 1996). "Structure and Function of HIV-1 Vpu" (pdf). Los Alamos National Laboratory. 
  7. ^ Andrew A, Strebel K (October 2010). "HIV-1 Vpu targets cell surface markers CD4 and BST-2 through distinct mechanisms". Mol. Aspects Med. 31 (5): 407–17. doi:10.1016/j.mam.2010.08.002. PMC 2967615. PMID 20858517. 
  8. ^ Andrew AJ, Miyagi E, Strebel K (March 2011). "Differential effects of human immunodeficiency virus type 1 Vpu on the stability of BST-2/tetherin". J. Virol. 85 (6): 2611–9. doi:10.1128/JVI.02080-10. PMC 3067951. PMID 21191020. 
  9. ^ Douglas JL, Viswanathan K, McCarroll MN, Gustin JK, Früh K, Moses AV (August 2009). "Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism". J. Virol. 83 (16): 7931–47. doi:10.1128/JVI.00242-09. PMC 2715753. PMID 19515779. 
  10. ^ Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K (December 2009). "HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes". J. Biol. Chem. 284 (50): 35060–72. doi:10.1074/jbc.M109.058305. PMC 2787367. PMID 19837671. 
  11. ^ Nomaguchi M, Fujita M, Adachi A (July 2008). "Role of HIV-1 Vpu protein for virus spread and pathogenesis". Microbes Infect. 10 (9): 960–7. doi:10.1016/j.micinf.2008.07.006. PMID 18672082. 
  12. ^ Cohen EA, Terwilliger EF, Sodroski JG, Haseltine WA (August 1988). "Identification of a protein encoded by the vpu gene of HIV-1". Nature 334 (6182): 532–4. doi:10.1038/334532a0. PMID 3043230. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR008187

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The Vpu protein contains an N-terminal transmembrane spanning region and a C-terminal cytoplasmic region. The HIV-1 Vpu protein stimulates virus production by enhancing the release of viral particles from infected cells. The VPU protein binds specifically to CD4.

Literature references

  1. Kobinger GP, Mouland AJ, Lalonde JP, Forget J, Cohen EA; , Gene Ther 1997;4:868-874.: Enhancement of retroviral production from packaging cell lines expressing the human immunodeficiency type 1 VPU gene. PUBMED:9338017 EPMC:9338017

  2. Bour S, Schubert U, Strebel K; , J Virol 1995;69:1510-1520.: The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: implications for the mechanism of degradation. PUBMED:7853484 EPMC:7853484

  3. Willbold D, Hoffmann S, Rosch P; , Eur J Biochem 1997;245:581-588.: Secondary structure and tertiary fold of the human immunodeficiency virus protein U (Vpu) cytoplasmic domain in solution. PUBMED:9182993 EPMC:9182993

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR008187

The human immunodeficiency virus type 1 Vpu transmembrane protein is required for the induction of degradation human CD4 receptor degradation in the endoplasmic reticulum, and for the enhancement of virus particle release from the plasma membrane of infected cells. The cytoplasmic domain of Vpu directly interacts with the CD4 receptor, targeting it for proteasome degradation [PUBMED:7853484]. The cytoplasmic domain encompasses the C-terminal half of the 81-residue protein, and is comprised of a few helical turns without an apparent hydrophobic core [PUBMED:9182993]. The transmembrane domain of Vpu, found towards the N terminus, forms a cation-selective ion channel and is responsible for the enhancement of virus particle release [PUBMED:14529626].

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Seed source: Swiss-Prot
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 16
Number in full: 6152
Average length of the domain: 71.70 aa
Average identity of full alignment: 65 %
Average coverage of the sequence by the domain: 97.50 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.6 23.6
Trusted cut-off 23.6 23.6
Noise cut-off 23.5 23.5
Model length: 81
Family (HMM) version: 14
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Species distribution

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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Vpu domain has been found. There are 8 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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