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O41801 (TAT_HV19N) Reviewed, UniProtKB/Swiss-Prot

Last modified February 19, 2014. Version 69. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Protein Tat
Alternative name(s):
Transactivating regulatory protein
OrganismHuman immunodeficiency virus type 1 group M subtype G (isolate 92NG083) (HIV-1)
Taxonomic identifier388825 [NCBI]
Taxonomic lineageVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
Virus hostHomo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length101 AA.
Sequence statusComplete.
Protein existenceInferred 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 nucleushost 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 processApoptosis
Host-virus interaction
Inhibition of host innate immune response by virus
Inhibition of host interferon signaling pathway by virus
Modulation of host chromatin by virus
Modulation of host PP1 activity by virus
Transcription
Transcription regulation
Viral immunoevasion
   Cellular componentHost cytoplasm
Host nucleus
Secreted
   Coding sequence diversityAlternative splicing
   DiseaseAIDS
   LigandMetal-binding
RNA-binding
Zinc
   Molecular functionActivator
   PTMAcetylation
Isopeptide bond
Methylation
Phosphoprotein
Ubl conjugation
Gene Ontology (GO)
   Biological_processapoptotic 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

suppression by virus of host type I interferon-mediated signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componenthost cell cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

host cell nucleolus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionRNA 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: O41801-1)

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: O41801-2)

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 101101Protein Tat
PRO_0000244846

Regions

Region1 – 4848Transactivation By similarity
Region1 – 2424Interaction with human CREBBP By similarity
Region22 – 3716Cysteine-rich By similarity
Region38 – 4811Core By similarity
Region49 – 8638Interaction with the host capping enzyme RNGTT By similarity
Motif49 – 579Nuclear localization signal, RNA-binding (TAR), and protein transduction By similarity
Motif78 – 803Cell attachment site Potential

Sites

Site111Essential for Tat's translocation through the endosomal membrane By similarity

Amino acid modifications

Modified residue281N6-acetyllysine; by host PCAF By similarity
Modified residue501N6-acetyllysine; by host EP300 and GCN5L2 By similarity
Modified residue511N6-acetyllysine; by host EP300 and GCN5L2 By similarity
Modified residue521Asymmetric dimethylarginine; by host PRMT6 By similarity
Modified residue531Asymmetric dimethylarginine; by host PRMT6 By similarity
Cross-link71Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity

Natural variations

Alternative sequence73 – 10129Missing in isoform Short.
VSP_022401

Sequences

Sequence LengthMass (Da)Tools
Isoform Long [UniParc].

Last modified January 1, 1998. Version 1.
Checksum: 840A21DDE209F9C9

FASTA10111,253
        10         20         30         40         50         60 
MDPVDPKLEP WNHPGSQPTT PCNKCYCKVC CWHCQVCFLN KGLGISYGRK KRRPRRGTPQ 

        70         80         90        100 
GSKDHQNPVP KQPLPITSGN PTGSEKPKKE VASKTETDPL D 

« Hide

Isoform Short [UniParc].

Checksum: EB719CD338235788
Show »

FASTA728,234

References

[1]"A comprehensive panel of near-full-length clones and reference sequences for non-subtype B isolates of human immunodeficiency virus type 1."
Gao F., Robertson D.L., Carruthers C.D., Morrison S.G., Jian B., Chen Y., Barre-Sinoussi F., Girard M., Srinivasan A., Abimiku A.G., Shaw G.M., Sharp P.M., Hahn B.H.
J. Virol. 72:5680-5698(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Strain: 92NG083.
[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
U88826 Genomic DNA. Translation: AAC32656.1.

3D structure databases

ProteinModelPortalO41801.
SMRO41801. Positions 1-86.
ModBaseSearch...
MobiDBSearch...

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Family and domain databases

Gene3D4.10.20.10. 1 hit.
InterProIPR001831. IV_Tat.
[Graphical view]
PfamPF00539. Tat. 1 hit.
[Graphical view]
PRINTSPR00055. HIVTATDOMAIN.
ProtoNetSearch...

Entry information

Entry nameTAT_HV19N
AccessionPrimary (citable) accession number: O41801
Entry history
Integrated into UniProtKB/Swiss-Prot: July 11, 2006
Last sequence update: January 1, 1998
Last modified: February 19, 2014
This is version 69 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programViral Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families