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Q75005

- TAT_HV1ET

UniProt

Q75005 - TAT_HV1ET

Protein

Protein Tat

Gene
N/A
Organism
Human immunodeficiency virus type 1 group M subtype C (isolate ETH2220) (HIV-1)
Status
Reviewed - Annotation score: 4 out of 5- Protein inferred from homologyi
  1. Functioni

    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.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.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei11 – 111Essential for Tat's translocation through the endosomal membraneBy similarity

    GO - Molecular functioni

    1. metal ion binding Source: UniProtKB-KW
    2. RNA binding Source: UniProtKB-KW
    3. sequence-specific DNA binding transcription factor activity Source: InterPro

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. modulation by virus of host chromatin organization Source: UniProtKB-KW
    3. modulation by virus of host PP1 activity Source: UniProtKB-KW
    4. suppression by virus of host type I interferon-mediated signaling pathway Source: UniProtKB-KW
    5. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Apoptosis, 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

    Keywords - Ligandi

    Metal-binding, RNA-binding, Zinc

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Protein Tat
    Alternative name(s):
    Transactivating regulatory protein
    OrganismiHuman immunodeficiency virus type 1 group M subtype C (isolate ETH2220) (HIV-1)
    Taxonomic identifieri388796 [NCBI]
    Taxonomic lineageiVirusesRetro-transcribing virusesRetroviridaeOrthoretrovirinaeLentivirusPrimate lentivirus group
    Virus hostiHomo sapiens (Human) [TaxID: 9606]
    ProteomesiUP000007694: Genome

    Subcellular locationi

    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.By similarity

    GO - Cellular componenti

    1. host cell cytoplasm Source: UniProtKB-SubCell
    2. host cell nucleolus Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Host cytoplasm, Host nucleus, Secreted

    Pathology & Biotechi

    Keywords - Diseasei

    AIDS

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 4242Protein TatPRO_0000244851Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei28 – 281N6-acetyllysine; by host PCAFBy similarity

    Post-translational modificationi

    Acetylation by EP300, CREBBP, GCN5L2/GCN5 and PCAF regulates the transactivation activity of Tat. PCAF-mediated acetylation of Lys-28 enhances Tat's binding to CCNT1 By similarity.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.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

    Keywords - PTMi

    Acetylation, Methylation, Phosphoprotein, Ubl conjugation

    Interactioni

    Subunit structurei

    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 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 By similarity.By similarity

    Structurei

    3D structure databases

    ProteinModelPortaliQ75005.
    SMRiQ75005. Positions 1-42.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 2424Interaction with human CREBBPBy similarityAdd
    BLAST
    Regioni22 – 3716Cysteine-richBy similarityAdd
    BLAST

    Domaini

    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.By similarity
    The Cys-rich region may bind 2 zinc ions Potential. This region is involved in binding to KAT5 By similarity.By similarityCurated
    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.By similarity

    Sequence similaritiesi

    Belongs to the lentiviruses Tat family.Curated

    Family and domain databases

    Gene3Di4.10.20.10. 1 hit.
    InterProiIPR001831. IV_Tat.
    [Graphical view]
    PfamiPF00539. Tat. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform Long (identifier: Q75005-1) [UniParc]FASTAAdd to Basket

    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.

    « Hide

    MEPVDPNLEP WNHPGSQPKT ACNQCYCKKC SYHCLVCFLT KA           42
    Length:42
    Mass (Da):4,786
    Last modified:November 1, 1996 - v1
    Checksum:i583F4346E07C007B
    GO
    Isoform Short (identifier: Q75005-2)

    Sequence is not available

    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.

    Length:
    Mass (Da):

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U46016 Genomic DNA. Translation: AAB36504.1.

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U46016 Genomic DNA. Translation: AAB36504.1 .

    3D structure databases

    ProteinModelPortali Q75005.
    SMRi Q75005. Positions 1-42.
    ModBasei Search...
    MobiDBi Search...

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Family and domain databases

    Gene3Di 4.10.20.10. 1 hit.
    InterProi IPR001831. IV_Tat.
    [Graphical view ]
    Pfami PF00539. Tat. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Full-length sequence of an ethiopian human immunodeficiency virus type 1 (HIV-1) isolate of genetic subtype C."
      Salminen M.O., Johansson B., Sonnerborg A., Ayehunie S., Gotte D., Leinikki P., Burke D.S., McCutchan F.E.
      AIDS Res. Hum. Retroviruses 12:1329-1339(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    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. Cited for: REVIEW.

    Entry informationi

    Entry nameiTAT_HV1ET
    AccessioniPrimary (citable) accession number: Q75005
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 11, 2006
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 69 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).
    This truncated variant has a premature stop codon. It may have arose as a consequence of tissue culture passaging.

    Keywords - Technical termi

    Complete proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3