P04618 (REV_HV1H2) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein Rev

Alternative name(s):
ART/TRS
Anti-repression transactivator
Regulator of expression of viral proteins

Gene names

Name:

rev

Organism

Human immunodeficiency virus type 1 group M subtype B (isolate HXB2) (HIV-1) [Reference proteome]

Taxonomic identifier

11706 [NCBI]

Taxonomic lineage

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

Virus host

Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	116 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 By similarity. Interacts with DDX1; the interaction is necessary for proper subcellular localization of this protein.
Subunit structure	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 By similarity. Ref.5
Subcellular location	Host nucleus › host nucleolus. Host cytoplasm. Note: The presence of both nuclear import and nuclear export signals leads to continuous shuttling between the nucleus and cytoplasm By similarity.
Domain	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 By similarity.
Post-translational modification	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. Ref.2 Ref.3 Ref.4 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.
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).
Sequence similarities	Belongs to the HIV-1 REV protein family.

Ontologies

Keywords
Biological process	Host-virus interaction Transport mRNA transport
Cellular component	Host cytoplasm Host nucleus
Disease	AIDS
Ligand	RNA-binding
PTM	Methylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	RNA-dependent DNA replication Traceable author statement. Source: Reactome entry into host cell Traceable author statement. Source: Reactome mRNA transport Inferred from electronic annotation. Source: UniProtKB-KW uncoating of virus Traceable author statement. Source: Reactome virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Traceable author statement. Source: Reactome host cell cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell host cell nucleolus Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	RNA binding Inferred from electronic annotation. Source: UniProtKB-KW sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CHCHD1	Q96BP2	3	EBI-6164309,EBI-5454898	From a different organism.
IK	Q13123	3	EBI-6164309,EBI-713456	From a different organism.
MITD1	Q8WV92	2	EBI-6164309,EBI-2691489	From a different organism.
MRPS9	P82933	2	EBI-6164309,EBI-721385	From a different organism.
SSBP1	Q04837	3	EBI-6164309,EBI-353460	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 116	116	Protein Rev		PRO_0000085279
Regions
	Region	18 – 26	9	Homomultimerization By similarity
	Motif	34 – 50	17	Nuclear localization signal and RNA-binding (RRE) By similarity
	Motif	73 – 84	12	Nuclear export signal and binding to XPO1 By similarity
	Compositional bias	38 – 50	13	Poly-Arg
Amino acid modifications
	Modified residue	5	1	Phosphoserine; by host CK2 Ref.2
	Modified residue	8	1	Phosphoserine; by host CK2 Ref.2
	Modified residue	92	1	Phosphoserine; by host By similarity
	Modified residue	99	1	Phosphoserine; by host By similarity

Sequences

	Sequence		Length	Mass (Da)
	P04618 [UniParc]. Last modified August 13, 1987. Version 1. Checksum: 4BCF5059C9A7F3B2	FASTA	116	13,075
	10 20 30 40 50 60 MAGRSGDSDE ELIRTVRLIK LLYQSNPPPN PEGTRQARRN RRRRWRERQR QIHSISERIL 70 80 90 100 110 GTYLGRSAEP VPLQLPPLER LTLDCNEDCG TSGTQGVGSP QILVESPTVL ESGTKE

References

[1]	"Complete nucleotide sequences of functional clones of the AIDS virus." Ratner L., Fisher A., Jagodzinski L.L., Mitsuya H., Liou R.-S., Gallo R.C., Wong-Staal F. AIDS Res. Hum. Retroviruses 3:57-69(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Phosphorylation of HIV-1 Rev protein: implication of protein kinase CK2 and pro-directed kinases." Meggio F., D'Agostino D.M., Ciminale V., Chieco-Bianchi L., Pinna L.A. Biochem. Biophys. Res. Commun. 226:547-554(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-5 AND SER-8 BY CK2.
[3]	"Unique features of HIV-1 Rev protein phosphorylation by protein kinase CK2 ('casein kinase-2')." Marin O., Sarno S., Boschetti M., Pagano M.A., Meggio F., Ciminale V., D'Agostino D.M., Pinna L.A. FEBS Lett. 481:63-67(2000) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY CK2.
[4]	"HIV-1 Rev transactivator: a beta-subunit directed substrate and effector of protein kinase CK2." Meggio F., Marin O., Boschetti M., Sarno S., Pinna L.A. Mol. Cell. Biochem. 227:145-151(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY CK2.
[5]	"A DEAD box protein facilitates HIV-1 replication as a cellular co-factor of Rev." Fang J., Kubota S., Yang B., Zhou N., Zhang H., Godbout R., Pomerantz R.J. Virology 330:471-480(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DDX1.
[6]	"The ins and outs of HIV Rev." Hope T.J. Arch. Biochem. Biophys. 365:186-191(1999) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
+	Additional computationally mapped references.

Web resources

BioAfrica HIV proteomics resource

Rev entry

Cross-references

Sequence databases
EMBL GenBank DDBJ	K03455 Genomic RNA. Translation: AAB50257.1.
PIR	JC4968.
RefSeq	NP_057854.1. NC_001802.1.
3D structure databases
ProteinModelPortal	P04618.
ModBase	Search...
Protein-protein interaction databases
IntAct	P04618. 18 interactions.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	155908.
Enzyme and pathway databases
Reactome	REACT_116125. Disease.
Family and domain databases
InterPro	IPR000625. REV_protein. [Graphical view]
Pfam	PF00424. REV. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P04618.
ChEMBL	CHEMBL1293282.

Entry information

Entry name

REV_HV1H2

Accession

Primary (citable) accession number: P04618

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	August 13, 1987
Last modified:	May 1, 2013
This is version 91 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program