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Protein

Protein Rev

Gene

rev

Organism
Human immunodeficiency virus type 1 group M subtype B (isolate HXB3) (HIV-1)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Escorts unspliced or incompletely spliced viral pre-mRNAs (late transcripts) out of the nucleus of infected cells. These pre-mRNAs carry a recognition sequence called Rev responsive element (RRE) located in the env gene, that is not present in fully spliced viral mRNAs (early transcripts). This function is essential since most viral proteins are translated from unspliced or partially spliced pre-mRNAs which cannot exit the nucleus by the pathway used by fully processed cellular mRNAs. Rev itself is translated from a fully spliced mRNA that readily exits the nucleus. Rev's nuclear localization signal (NLS) binds directly to KPNB1/Importin beta-1 without previous binding to KPNA1/Importin alpha-1. KPNB1 binds to the GDP bound form of RAN (Ran-GDP) and targets Rev to the nucleus. In the nucleus, the conversion from Ran-GDP to Ran-GTP dissociates Rev from KPNB1 and allows Rev's binding to the RRE in viral pre-mRNAs. Rev multimerization on the RRE via cooperative assembly exposes its nuclear export signal (NES) to the surface. Rev can then form a complex with XPO1/CRM1 and Ran-GTP, leading to nuclear export of the complex. Conversion from Ran-GTP to Ran-GDP mediates dissociation of the Rev/RRE/XPO1/RAN complex, so that Rev can return to the nucleus for a subsequent round of export. Beside KPNB1, also seems to interact with TNPO1/Transportin-1, RANBP5/IPO5 and IPO7/RANBP7 for nuclear import. The nucleoporin-like HRB/RIP is an essential cofactor that probably indirectly interacts with Rev to release HIV RNAs from the perinuclear region to the cytoplasm.3 Publications

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Host-virus interaction, mRNA transport, Transport

Keywords - Ligandi

RNA-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Protein Rev
Alternative name(s):
ART/TRS
Anti-repression transactivator
Regulator of expression of viral proteins
Gene namesi
Name:rev
OrganismiHuman immunodeficiency virus type 1 group M subtype B (isolate HXB3) (HIV-1)
Taxonomic identifieri11707 [NCBI]
Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostiHomo sapiens (Human) [TaxID: 9606]

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Host cytoplasm, Host nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi4 – 52RS → DL: Partial loss of expression of unspliced viral transcripts. No effect on phosphorylation. 1 Publication
Mutagenesisi8 – 92SD → DL: No effect on expression of unspliced viral transcripts. Decreased phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi17 – 171R → D: No effect on expression of unspliced viral transcripts. No effect on phosphorylation. Expressed in nucleus and slightly in cytoplasm. 1 Publication
Mutagenesisi23 – 264YQSN → DQDL: Complete loss of expression of unspliced viral transcripts. No effect on phosphorylation. Expressed in nucleus and slightly in cytoplasm. 1 Publication
Mutagenesisi38 – 392RR → DL: Complete loss of expression of unspliced viral transcripts. Decreased phosphorylation. Expressed in cytoplasm and slightly in nucleus. 1 Publication
Mutagenesisi41 – 444RRRR → DL: Complete loss of expression of unspliced viral transcripts. Complete loss of phosphorylation. Expressed in cytoplasm and slightly in nucleus. 1 Publication
Mutagenesisi54 – 563SIS → I: Complete loss of expression of unspliced viral transcripts. No effect on phosphorylation. Expressed in nucleus and slightly in cytoplasm. 1 Publication
Mutagenesisi61 – 622ST → DL: No effect on expression of unspliced viral transcripts. No effect on phosphorylation. Expressed in nucleus and slightly in cytoplasm. 1 Publication
Mutagenesisi67 – 682SA → DL: No effect on expression of unspliced viral transcripts. No effect on phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi78 – 792LE → DL: Complete loss of expression of unspliced viral transcripts. No effect on phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi91 – 922TS → DL: No effect on expression of unspliced viral transcripts. No effect on phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi92 – 921S → R: Decreased phosphorylation. 1 Publication
Mutagenesisi99 – 1002SP → DL: No effect on expression of unspliced viral transcripts. Decreased phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi99 – 991S → I: Decreased phosphorylation. 1 Publication
Mutagenesisi106 – 1094SPTI → DLTV: No effect on expression of unspliced viral transcripts. No effect on phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi106 – 1061S → F: Almost no effect on phosphorylation. 1 Publication
Mutagenesisi112 – 1132SG → DL: No effect on expression of unspliced viral transcripts. No effect on phosphorylation. No effect on subcellular location. 1 Publication
Mutagenesisi112 – 1121S → L: Almost no effect on phosphorylation. 1 Publication

Keywords - Diseasei

AIDS

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 116116Protein RevPRO_0000085262Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei5 – 51Phosphoserine; by host CK2By similarity
Modified residuei8 – 81Phosphoserine; by host CK2By similarity
Modified residuei92 – 921Phosphoserine; by host1 Publication
Modified residuei99 – 991Phosphoserine; by host1 Publication

Post-translational modificationi

Phosphorylated by protein kinase CK2. Presence of, and maybe binding to the N-terminus of the regulatory beta subunit of CK2 is necessary for CK2-mediated Rev's phosphorylation (By similarity).By similarity
Asymmetrically arginine dimethylated at one site by host PRMT6. Methylation impairs the RNA-binding activity and export of viral RNA from the nucleus to the cytoplasm (By similarity).By similarity

Keywords - PTMi

Methylation, Phosphoprotein

PTM databases

iPTMnetiP69718.

Interactioni

Subunit structurei

Homomultimer; when bound to the RRE. Multimeric assembly is essential for activity and may involve XPO1. Binds to human KPNB1, XPO1, TNPO1, RANBP5 and IPO7. Interacts with the viral Integrase. Interacts with human KHDRBS1. Interacts with human NAP1; this interaction decreases Rev multimerization and stimulates its activity. Interacts with human DEAD-box helicases DDX3 and DDX24; these interactions may serve for viral RNA export to the cytoplasm and packaging, respectively. Interacts with human PSIP1; this interaction may inhibit HIV-1 DNA integration by promoting dissociation of the Integrase-LEDGF/p75 complex.12 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
gag-polP045858EBI-8540156,EBI-3989067From a different organism.

Protein-protein interaction databases

DIPiDIP-61764N.
IntActiP69718. 1 interaction.
MINTiMINT-8053053.

Structurei

Secondary structure

1
116
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi11 – 2414Combined sources
Helixi35 – 6329Combined sources
Helixi65 – 673Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3LPHX-ray2.50A/B/C/D1-70[»]
4PMIX-ray3.20B/C1-70[»]
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni18 – 269Homomultimerization

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi34 – 5017Nuclear localization signal and RNA-binding (RRE)3 PublicationsAdd
BLAST
Motifi73 – 8412Nuclear export signal and binding to XPO1Add
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi38 – 5013Poly-ArgAdd
BLAST

Domaini

The RNA-binding motif binds to the RRE, a 240 bp stem-and-loop structure present in incompletely spliced viral pre-mRNAs. This region also contains the NLS which mediates nuclear localization via KPNB1 binding and, when the N-terminal sequence is present, nucleolar targeting. These overlapping functions prevent Rev bound to RRE from undesirable return to the nucleus. When Rev binds the RRE, the NLS becomes masked while the NES remains accessible. The leucine-rich NES mediates binding to human XPO1.

Sequence similaritiesi

Belongs to the HIV-1 REV protein family.Curated

Family and domain databases

InterProiIPR000625. REV_protein.
[Graphical view]
PfamiPF00424. REV. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P69718-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAGRSGDSDE DLLKAVRLIK FLYQSNPPPN PEGTRQARRN RRRRWRERQR
60 70 80 90 100
QIHSISERIL STYLGRSAEP VPLQLPPLER LTLDCNEDCG TSGTQGVGSP
110
QILVESPTIL ESGAKE
Length:116
Mass (Da):13,051
Last modified:August 13, 1987 - v1
Checksum:iF3DA2E7AF302FBDF
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M14100 Genomic RNA. Translation: AAA44677.1.
PIRiS33983.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M14100 Genomic RNA. Translation: AAA44677.1.
PIRiS33983.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3LPHX-ray2.50A/B/C/D1-70[»]
4PMIX-ray3.20B/C1-70[»]
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-61764N.
IntActiP69718. 1 interaction.
MINTiMINT-8053053.

PTM databases

iPTMnetiP69718.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Family and domain databases

InterProiIPR000625. REV_protein.
[Graphical view]
PfamiPF00424. REV. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "HTLV-III env gene products synthesized in E. coli are recognized by antibodies present in the sera of AIDS patients."
    Crowl R., Ganguly K., Gordon M., Conroy R., Schaber M., Kramer R., Shaw G.M., Wong-Staal F., Reddy E.P.
    Cell 41:979-986(1985) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
  2. "Phosphorylation of the rev gene product of human immunodeficiency virus type 1."
    Hauber J., Bouvier M., Malim M.H., Cullen B.R.
    J. Virol. 62:4801-4804(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION.
  3. "Functional significance of phosphorylation to the human immunodeficiency virus Rev protein."
    Cochrane A.W., Golub E., Volsky D., Ruben S., Rosen C.A.
    J. Virol. 63:4438-4440(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-92 AND SER-99, MUTAGENESIS OF SER-92; SER-99; SER-106 AND SER-112.
  4. "The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA."
    Malim M.H., Hauber J., Le S.-Y., Maizel J.V., Cullen B.R.
    Nature 338:254-257(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  5. "Functional dissection of the HIV-1 Rev trans-activator -- derivation of a trans-dominant repressor of Rev function."
    Malim M.H., Bohnlein S., Hauber J., Cullen B.R.
    Cell 58:205-214(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, MUTAGENESIS OF 4-ARG-SER-5; 8-SER-ASP-9; ARG-17; 23-TYR--ASN-26; 38-ARG-ARG-39; 41-ARG--ARG-44; 54-SER--SER-56; 61-SER-THR-62; 67-SER-THR-68; 78-LEU-GLU-79; 91-THR-SER-92; 99-SER-PRO-100; 106-SER--ILE-109 AND 112-SER-GLY-113.
  6. "Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function."
    Cochrane A.W., Perkins A., Rosen C.A.
    J. Virol. 64:881-885(1990) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL.
  7. "HIV-1 structural gene expression requires the binding of multiple Rev monomers to the viral RRE: implications for HIV-1 latency."
    Malim M.H., Cullen B.R.
    Cell 65:241-248(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT, RNA-BINDING.
  8. "Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: a dual function for an arginine-rich binding motif."
    Zapp M.L., Hope T.J., Parslow T.G., Green M.R.
    Proc. Natl. Acad. Sci. U.S.A. 88:7734-7738(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT, RNA-BINDING.
  9. "Functional mapping of the human immunodeficiency virus type 1 Rev RNA binding domain: new insights into the domain structure of Rev and Rex."
    Boehnlein E., Berger J., Hauber J.
    J. Virol. 65:7051-7055(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: RNA-BINDING.
  10. "Specific binding of a basic peptide from HIV-1 Rev."
    Kjems J., Calnan B.J., Frankel A.D., Sharp P.A.
    EMBO J. 11:1119-1129(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: RNA-BINDING.
  11. "The HIV-1 Rev trans-activator shuttles between the nucleus and the cytoplasm."
    Meyer B.E., Malim M.H.
    Genes Dev. 8:1538-1547(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  12. "Identification of a signal for rapid export of proteins from the nucleus."
    Wen W., Meinkoth J.L., Tsien R.Y., Taylor S.S.
    Cell 82:463-473(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEAR EXPORT SIGNAL.
  13. "Nuclear export of late HIV-1 mRNAs occurs via a cellular protein export pathway."
    Fridell R.A., Bogerd H.P., Cullen B.R.
    Proc. Natl. Acad. Sci. U.S.A. 93:4421-4424(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  14. "Sensitive in vitro analysis of HIV-1 Rev multimerization."
    Brice P.C., Kelley A.C., Butler P.J.G.
    Nucleic Acids Res. 27:2080-2085(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT.
  15. "Evidence for specific nucleocytoplasmic transport pathways used by leucine-rich nuclear export signals."
    Elfgang C., Rosorius O., Hofer L., Jaksche H., Hauber J., Bevec D.
    Proc. Natl. Acad. Sci. U.S.A. 96:6229-6234(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEAR EXPORT SIGNAL.
  16. "The arginine-rich domains present in human immunodeficiency virus type 1 Tat and Rev function as direct importin beta-dependent nuclear localization signals."
    Truant R., Cullen B.R.
    Mol. Cell. Biol. 19:1210-1217(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEAR LOCALIZATION SIGNAL, INTERACTION WITH HOST KPNB1.
  17. "Expression of exogenous Sam68, the 68-kilodalton SRC-associated protein in mitosis, is able to alleviate impaired Rev function in astrocytes."
    Li J., Liu Y., Park I.W., He J.J.
    J. Virol. 76:4526-4535(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST KHDRBS1.
  18. "The carboxy-terminal region of the human immunodeficiency virus type 1 protein Rev has multiple roles in mediating CRM1-related Rev functions."
    Hakata Y., Yamada M., Mabuchi N., Shida H.
    J. Virol. 76:8079-8089(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST XPO1, SUBUNIT.
  19. "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function."
    Yedavalli V.S., Neuveut C., Chi Y.-H., Kleiman L., Jeang K.-T.
    Cell 119:381-392(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST DDX3X.
  20. "hRIP, a cellular cofactor for Rev function, promotes release of HIV RNAs from the perinuclear region."
    Sanchez-Velar N., Udofia E.B., Yu Z., Zapp M.L.
    Genes Dev. 18:23-34(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  21. "Multiple importins function as nuclear transport receptors for the Rev protein of human immunodeficiency virus type 1."
    Arnold M., Nath A., Hauber J., Kehlenbach R.H.
    J. Biol. Chem. 281:20883-20890(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST KPNB1; TNPO1; RANBP5 AND IPO7.
  22. Cited for: REVIEW.
  23. "Interaction between HIV-1 Rev and integrase proteins: a basis for the development of anti-HIV peptides."
    Rosenbluh J., Hayouka Z., Loya S., Levin A., Armon-Omer A., Britan E., Hizi A., Kotler M., Friedler A., Loyter A.
    J. Biol. Chem. 282:15743-15753(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH INTEGRASE.
  24. "The requirement of the DEAD-box protein DDX24 for the packaging of human immunodeficiency virus type 1 RNA."
    Ma J., Rong L., Zhou Y., Roy B.B., Lu J., Abrahamyan L., Mouland A.J., Pan Q., Liang C.
    Virology 375:253-264(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST DDX24.
  25. "Integration of HIV-1 DNA is regulated by interplay between viral rev and cellular LEDGF/p75 proteins."
    Levin A., Rosenbluh J., Hayouka Z., Friedler A., Loyter A.
    Mol. Med. 16:34-44(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST PSIP1.
  26. "Stable complex formation between HIV Rev and the nucleosome assembly protein, NAP1, affects Rev function."
    Cochrane A., Murley L.L., Gao M., Wong R., Clayton K., Brufatto N., Canadien V., Mamelak D., Chen T., Richards D., Zeghouf M., Greenblatt J., Burks C., Frappier L.
    Virology 388:103-111(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HOST NAP1.

Entry informationi

Entry nameiREV_HV1H3
AccessioniPrimary (citable) accession number: P69718
Secondary accession number(s): P04617
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: August 13, 1987
Last modified: March 16, 2016
This is version 64 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Miscellaneousi

Miscellaneous

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).

Keywords - Technical termi

3D-structure

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.