P04614 (TAT_HV1A2) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names	Recommended name: Protein Tat Alternative name(s): Transactivating regulatory protein
Organism	Human immunodeficiency virus type 1 group M subtype B (isolate ARV2/SF2) (HIV-1) [Complete proteome]
Taxonomic identifier	11685 [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	101 AA.
Sequence status	Complete.
Protein existence	Inferred from homology

General annotation (Comments)

Function	Nuclear transcriptional activator of viral gene expression, that is essential for viral transcription from the LTR promoter and replication. Acts as a sequence-specific molecular adapter, directing components of the cellular transcription machinery to the viral RNA to promote processive transcription elongation by the RNA polymerase II (RNA pol II) complex, thereby increasing the level of full-length transcripts. In the absence of Tat, the RNA Pol II generates short or non-processive transcripts that terminate at approximately 60 bp from the initiation site. Tat associates with the CCNT1/cyclin-T1 component of the P-TEFb complex (CDK9 and CCNT1), which promotes RNA chain elongation. This binding increases Tat's affinity for a hairpin structure at the 5'-end of all nascent viral mRNAs referred to as the transactivation responsive RNA element (TAR RNA) and allows Tat/P-TEFb complex to bind cooperatively to TAR RNA. The CDK9 component of P-TEFb and other Tat-activated kinases hyperphosphorylate the C-terminus of RNA Pol II that becomes stabilized and much more processive. Other factors such as HTATSF1/Tat-SF1, SUPT5H/SPT5, and HTATIP2 are also important for Tat's function. Besides its effect on RNA Pol II processivity, Tat induces chromatin remodeling of proviral genes by recruiting the histone acetyltransferases (HATs) CREBBP, EP300 and PCAF to the chromatin. This also contributes to the increase in proviral transcription rate, especially when the provirus integrates in transcriptionally silent region of the host genome. To ensure maximal activation of the LTR, Tat mediates nuclear translocation of NF-kappa-B. In this purpose, it activates EIF2AK2/PKR which, in turns, may phosphorylate and target to degradation the inhibitor IkappaB-alpha which normally retains NF-kappa-B in the cytoplasm of unstimulated cells. Through its interaction with TBP, Tat may be involved in transcription initiation as well. Interacts with the cellular capping enzyme RNGTT to mediate co-transcriptional capping of viral mRNAs. Tat protein exerts as well a positive feedback on the translation of its cognate mRNA. Tat can reactivate a latently infected cell by penetrating in it and transactivating its LTR promoter. In the cytoplasm, Tat is thought to act as a translational activator of HIV-1 mRNAs By similarity. Extracellular circulating Tat can be endocytosed by surrounding uninfected cells via the binding to several surface receptors such as CD26, CXCR4, heparan sulfate proteoglycans (HSPG) or LDLR. Neurons are rarely infected, but they internalize Tat via their LDLR. Endosomal low pH allows Tat to cross the endosome membrane to enter the cytosol and eventually further translocate into the nucleus, thereby inducing severe cell dysfunctions ranging from cell activation to cell death. Through its interaction with nuclear HATs, Tat is potentially able to control the acetylation-dependent cellular gene expression. Tat seems to inhibit the HAT activity of KAT5/Tip60 and TAF1, and consequently modify the expression of specific cellular genes. Modulates the expression of many cellular genes involved in cell survival, proliferation or in coding for cytokines (such as IL10) or cytokine receptors. May be involved in the derepression of host interleukin IL2 expression. Mediates the activation of cyclin-dependent kinases and dysregulation of microtubule network. Tat plays a role in T-cell and neurons apoptosis. Tat induced neurotoxicity and apoptosis probably contribute to neuroAIDS. Host extracellular matrix metalloproteinase MMP1 cleaves Tat and decreases Tat's mediated neurotoxicity. Circulating Tat also acts as a chemokine-like and/or growth factor-like molecule that binds to specific receptors on the surface of the cells, affecting many cellular pathways. In the vascular system, Tat binds to ITGAV/ITGB3 and ITGA5/ITGB1 integrins dimers at the surface of endothelial cells and competes with bFGF for heparin-binding sites, leading to an excess of soluble bFGF. Binds to KDR/VEGFR-2. All these Tat-mediated effects enhance angiogenesis in Kaposi's sarcoma lesions By similarity.
Subunit structure	Interacts with host CCNT1. Associates with the P-TEFb complex composed at least of Tat, P-TEFb (CDK9 and CCNT1), TAR RNA, RNA Pol II. Recruits the HATs CREBBP, TAF1/TFIID, EP300, PCAF and GCN5L2. Interacts with host KAT5/Tip60; this interaction targets the latter to degradation. Interacts with the host deacetylase SIRT1. Interacts with host capping enzyme RNGTT; this interaction stimulates RNGTT. Binds to host KDR, and to the host integrins ITGAV/ITGB3 and ITGA5/ITGB1. Interacts with host KPNB1/importin beta-1 without previous binding to KPNA1/importin alpha-1. Interacts with EIF2AK2. Interacts with host nucleosome assembly protein NAP1L1; this interaction may be required for the transport of Tat within the nucleus, since the two proteins interact at the nuclear rim. Interacts with host C1QBP/SF2P32; this interaction involves lysine-acetylated Tat. Interacts with the host chemokine receptors CCR2, CCR3 and CXCR4. Interacts with host DPP4/CD26; this interaction may trigger an anti-proliferative effect. Interacts with host LDLR. Interacts with the host extracellular matrix metalloproteinase MMP1. Interacts with host PRMT6; this interaction mediates Tat's methylation. Interacts with, and is ubiquitinated by MDM2/Hdm2. Interacts with host PSMC3 and HTATIP2. Interacts with STAB1; this interaction may overcome SATB1-mediated repression of IL2 and IL2RA (interleukin) in T cells by binding to the same domain than HDAC1. Interacts (when acetylated on Lys-50 and Lys-51) with human CDK13, thereby increasing HIV-1 mRNA splicing and promoting the production of the doubly spliced HIV-1 protein Nef By similarity.
Subcellular location	Host nucleus › host nucleolus. Host cytoplasm. Secreted. Note: Probably localizes to both nuclear and nucleolar compartments. Nuclear localization is mediated through the interaction of the nuclear localization signal with importin KPNB1. Secretion occurs through a Golgi-independent pathway. Tat is released from infected cells to the extracellular space where it remains associated to the cell membrane, or is secreted into the cerebrospinal fluid and sera. Extracellular Tat can be endocytosed by surrounding uninfected cells via binding to several receptors depending on the cell type By similarity.
Domain	The transactivation domain mediates the interaction with CCNT1, GCN5L2, and MDM2 By similarity. The Arg-rich RNA-binding region binds the TAR RNA. This region also mediates the nuclear localization through direct binding to KPNB1 and is involved in Tat's transfer across cell membranes (protein transduction). The same region is required for the interaction with EP300, PCAF, EIF2AK2 and KDR By similarity. The Cys-rich region may bind 2 zinc ions Potential. This region is involved in binding to KAT5 By similarity. The cell attachment site mediates the interaction with ITGAV/ITGB3 and ITGA5/ITGB1 integrins, leading to vascular cell migration and invasion. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens By similarity.
Post-translational modification	Acetylation by EP300, CREBBP, GCN5L2/GCN5 and PCAF regulates the transactivation activity of Tat. EP300-mediated acetylation of Lys-50 promotes dissociation of Tat from the TAR RNA through the competitive binding to PCAF's bromodomain. In addition, the non-acetylated Tat's N-terminus can also interact with PCAF. PCAF-mediated acetylation of Lys-28 enhances Tat's binding to CCNT1. Lys-50 is deacetylated by SIRT1 By similarity. Phosphorylated by EIF2AK2 on serine and threonine residues adjacent to the basic region important for TAR RNA binding and function. Phosphorylation of Tat by EIF2AK2 is dependent on the prior activation of EIF2AK2 by dsRNA By similarity. Asymmetrical arginine methylation by host PRMT6 seems to diminish the transactivation capacity of Tat and affects the interaction with host CCNT1 By similarity. Polyubiquitination by MDM2 does not target Tat to degradation, but activates its transactivation function and fosters interaction with CCNT1 and TAR RNA 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 lentiviruses Tat family.

Ontologies

Keywords
Biological process	Apoptosis Host-virus interaction Inhibition of host innate immune response by virus Inhibition of host interferon signaling pathway by virus Modulation of host PP1 activity by virus Modulation of host chromatin by virus Transcription Transcription regulation Viral immunoevasion
Cellular component	Host cytoplasm Host nucleus Secreted
Coding sequence diversity	Alternative splicing
Disease	AIDS
Ligand	Metal-binding RNA-binding Zinc
Molecular function	Activator
PTM	Acetylation Isopeptide bond Methylation Phosphoprotein Ubl conjugation
Technical term	Complete proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW modulation by virus of host PP1 activity Inferred from electronic annotation. Source: UniProtKB-KW modulation by virus of host chromatin organization Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of viral transcription Traceable author statement. Source: Reactome suppression by virus of host type I interferon-mediated signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW viral reproduction Traceable author statement. Source: Reactome
Cellular_component	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 metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: P04614-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: P04614-2)

The sequence of this isoform differs from the canonical sequence as follows:
     73-101: Missing.

Note: No experimental confirmation available. Expressed in the late stage of the infection cycle, when unspliced viral RNAs are exported to the cytoplasm by the viral Rev protein.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 101	101	Protein Tat		PRO_0000085345
Regions
	Region	1 – 48	48	Transactivation By similarity
	Region	1 – 24	24	Interaction with human CREBBP By similarity
	Region	22 – 37	16	Cysteine-rich By similarity
	Region	38 – 48	11	Core By similarity
	Region	49 – 86	38	Interaction with the host capping enzyme RNGTT By similarity
	Motif	49 – 57	9	Nuclear localization signal, RNA-binding (TAR), and protein transduction By similarity
	Motif	78 – 80	3	Cell attachment site Potential
Sites
	Site	11	1	Essential for Tat's translocation through the endosomal membrane By similarity
Amino acid modifications
	Modified residue	28	1	N6-acetyllysine; by host PCAF By similarity
	Modified residue	50	1	N6-acetyllysine; by host EP300 and GCN5L2 By similarity
	Modified residue	51	1	N6-acetyllysine; by host EP300 and GCN5L2 By similarity
	Modified residue	52	1	Asymmetric dimethylarginine; by host PRMT6 By similarity
	Modified residue	53	1	Asymmetric dimethylarginine; by host PRMT6 By similarity
	Cross-link	71		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Natural variations
	Alternative sequence	73 – 101	29	Missing in isoform Short.		VSP_022406

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified August 13, 1987. Version 1. Checksum: 1762370A3BD641FD	FASTA	101	11,557
	10 20 30 40 50 60 MEPVDPNLEP WKHPGSQPRT ACNNCYCKKC CFHCYACFTR KGLGISYGRK KRRQRRRAPQ 70 80 90 100 DSQTHQASLS KQPASQSRGD PTGPTESKKK VERETETDPF D
	Isoform Short [UniParc]. Checksum: 8137015B68249443	FASTA	72	8,385
	10 20 30 40 50 60 MEPVDPNLEP WKHPGSQPRT ACNNCYCKKC CFHCYACFTR KGLGISYGRK KRRQRRRAPQ 70 DSQTHQASLS KQ

References

[1]	"Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2)." Sanchez-Pescador R., Power M.D., Barr P.J., Steimer K.S., Stempien M.M., Brown-Shimer S.L., Gee W.W., Renard A., Randolph A., Levy J.A., Dina D., Luciw P.A. Science 227:484-492(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Decoding Tat: the biology of HIV Tat posttranslational modifications." Hetzer C., Dormeyer W., Schnolzer M., Ott M. Microbes Infect. 7:1364-1369(2005) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW, ALTERNATIVE SPLICING.
[3]	"The multiple functions of HIV-1 Tat: proliferation versus apoptosis." Peruzzi F. Front. Biosci. 11:708-717(2006) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[4]	"HIV tat and neurotoxicity." King J.E., Eugenin E.A., Buckner C.M., Berman J.W. Microbes Infect. 8:1347-1357(2006) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.

Cross-references

Sequence databases
EMBL GenBank DDBJ	K02007 Genomic RNA. Translation: AAB59879.1.
3D structure databases
ProteinModelPortal	P04614.
SMR	P04614. Positions 1-86.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Enzyme and pathway databases
Reactome	REACT_116125. Disease.
Family and domain databases
Gene3D	4.10.20.10. 1 hit.
InterPro	IPR001831. IV_Tat. [Graphical view]
Pfam	PF00539. Tat. 1 hit. [Graphical view]
PRINTS	PR00055. HIVTATDOMAIN.
ProtoNet	Search...

Entry information

Entry name

TAT_HV1A2

Accession

Primary (citable) accession number: P04614

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	August 13, 1987
Last modified:	April 3, 2013
This is version 87 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program