| Structural highlights
Function
[TAT_HV1BR] 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).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] 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).[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Tat is a viral protein essential for activation of the HIV genes and plays an important role in the HIV-induced immunodeficiency. We chemically synthesized a Tat protein (86 residues) with its six glycines C alpha labelled with 13C. This synthetic protein has the full Tat activity. Heteronuclear nuclear magnetic resonance (NMR) spectra and NOE back-calculation made possible the sequential assignment of the 86 spin systems. Consequently, 915 NMR restraints were identified and 272 of them turned out to be long range ([i-j] > 4), providing structural information on the whole Tat protein. The poor spectral dispersion of Tat NMR spectra does not allow an accurate structure to be determined as for other proteins studied by 2D NMR. Nevertheless, we were able to determine the folding for Tat protein at a 1-mM protein concentration in a 100 mM, pH 4.5 phosphate buffer. The two main Tat functional regions, the basic region and the cysteine-rich region, are well exposed to solvent while a part of the N-terminal region and the C-terminal region constitute the core of Tat Bru. The basic region adopts an extended structure while the cysteine-rich region is made up of two loops. Resolution of this structure was determinant to develop a drug design approach against Tat. The chemical synthesis of the drugs allowed the specific binding and the inhibition of Tat to be verified.
1H-13C nuclear magnetic resonance assignment and structural characterization of HIV-1 Tat protein.,Peloponese JM Jr, Gregoire C, Opi S, Esquieu D, Sturgis J, Lebrun E, Meurs E, Collette Y, Olive D, Aubertin AM, Witvrow M, Pannecouque C, De Clercq E, Bailly C, Lebreton J, Loret EP C R Acad Sci III. 2000 Oct;323(10):883-94. PMID:11098404[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wu-Baer F, Sigman D, Gaynor RB. Specific binding of RNA polymerase II to the human immunodeficiency virus trans-activating region RNA is regulated by cellular cofactors and Tat. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7153-7. PMID:7638159
- ↑ Parada CA, Roeder RG. Enhanced processivity of RNA polymerase II triggered by Tat-induced phosphorylation of its carboxy-terminal domain. Nature. 1996 Nov 28;384(6607):375-8. PMID:8934526 doi:10.1038/384375a0
- ↑ Demarchi F, d'Adda di Fagagna F, Falaschi A, Giacca M. Activation of transcription factor NF-kappaB by the Tat protein of human immunodeficiency virus type 1. J Virol. 1996 Jul;70(7):4427-37. PMID:8676466
- ↑ Ivanov D, Kwak YT, Nee E, Guo J, Garcia-Martinez LF, Gaynor RB. Cyclin T1 domains involved in complex formation with Tat and TAR RNA are critical for tat-activation. J Mol Biol. 1999 Apr 23;288(1):41-56. PMID:10329125 doi:10.1006/jmbi.1999.2663
- ↑ Demarchi F, Gutierrez MI, Giacca M. Human immunodeficiency virus type 1 tat protein activates transcription factor NF-kappaB through the cellular interferon-inducible, double-stranded RNA-dependent protein kinase, PKR. J Virol. 1999 Aug;73(8):7080-6. PMID:10400814
- ↑ Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Mol Cell Biol. 2000 Sep;20(18):6958-69. PMID:10958691
- ↑ Kim YK, Bourgeois CF, Isel C, Churcher MJ, Karn J. Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. Mol Cell Biol. 2002 Jul;22(13):4622-37. PMID:12052871
- ↑ Col E, Gilquin B, Caron C, Khochbin S. Tat-controlled protein acetylation. J Biol Chem. 2002 Oct 4;277(40):37955-60. Epub 2002 Aug 1. PMID:12154097 doi:10.1074/jbc.M206694200
- ↑ Kumar PP, Purbey PK, Ravi DS, Mitra D, Galande S. Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells. Mol Cell Biol. 2005 Mar;25(5):1620-33. PMID:15713622 doi:25/5/1620
- ↑ Raha T, Cheng SW, Green MR. HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. PLoS Biol. 2005 Feb;3(2):e44. Epub 2005 Feb 8. PMID:15719058 doi:10.1371/journal.pbio.0030044
- ↑ Gee K, Angel JB, Ma W, Mishra S, Gajanayaka N, Parato K, Kumar A. Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells. J Biol Chem. 2006 Oct 20;281(42):31647-58. Epub 2006 Aug 18. PMID:16920714 doi:M512109200
- ↑ Charnay N, Ivanyi-Nagy R, Soto-Rifo R, Ohlmann T, Lopez-Lastra M, Darlix JL. Mechanism of HIV-1 Tat RNA translation and its activation by the Tat protein. Retrovirology. 2009 Aug 11;6:74. doi: 10.1186/1742-4690-6-74. PMID:19671151 doi:10.1186/1742-4690-6-74
- ↑ Wu-Baer F, Sigman D, Gaynor RB. Specific binding of RNA polymerase II to the human immunodeficiency virus trans-activating region RNA is regulated by cellular cofactors and Tat. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7153-7. PMID:7638159
- ↑ Parada CA, Roeder RG. Enhanced processivity of RNA polymerase II triggered by Tat-induced phosphorylation of its carboxy-terminal domain. Nature. 1996 Nov 28;384(6607):375-8. PMID:8934526 doi:10.1038/384375a0
- ↑ Demarchi F, d'Adda di Fagagna F, Falaschi A, Giacca M. Activation of transcription factor NF-kappaB by the Tat protein of human immunodeficiency virus type 1. J Virol. 1996 Jul;70(7):4427-37. PMID:8676466
- ↑ Ivanov D, Kwak YT, Nee E, Guo J, Garcia-Martinez LF, Gaynor RB. Cyclin T1 domains involved in complex formation with Tat and TAR RNA are critical for tat-activation. J Mol Biol. 1999 Apr 23;288(1):41-56. PMID:10329125 doi:10.1006/jmbi.1999.2663
- ↑ Demarchi F, Gutierrez MI, Giacca M. Human immunodeficiency virus type 1 tat protein activates transcription factor NF-kappaB through the cellular interferon-inducible, double-stranded RNA-dependent protein kinase, PKR. J Virol. 1999 Aug;73(8):7080-6. PMID:10400814
- ↑ Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Mol Cell Biol. 2000 Sep;20(18):6958-69. PMID:10958691
- ↑ Kim YK, Bourgeois CF, Isel C, Churcher MJ, Karn J. Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. Mol Cell Biol. 2002 Jul;22(13):4622-37. PMID:12052871
- ↑ Col E, Gilquin B, Caron C, Khochbin S. Tat-controlled protein acetylation. J Biol Chem. 2002 Oct 4;277(40):37955-60. Epub 2002 Aug 1. PMID:12154097 doi:10.1074/jbc.M206694200
- ↑ Kumar PP, Purbey PK, Ravi DS, Mitra D, Galande S. Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells. Mol Cell Biol. 2005 Mar;25(5):1620-33. PMID:15713622 doi:25/5/1620
- ↑ Raha T, Cheng SW, Green MR. HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. PLoS Biol. 2005 Feb;3(2):e44. Epub 2005 Feb 8. PMID:15719058 doi:10.1371/journal.pbio.0030044
- ↑ Gee K, Angel JB, Ma W, Mishra S, Gajanayaka N, Parato K, Kumar A. Intracellular HIV-Tat expression induces IL-10 synthesis by the CREB-1 transcription factor through Ser133 phosphorylation and its regulation by the ERK1/2 MAPK in human monocytic cells. J Biol Chem. 2006 Oct 20;281(42):31647-58. Epub 2006 Aug 18. PMID:16920714 doi:M512109200
- ↑ Charnay N, Ivanyi-Nagy R, Soto-Rifo R, Ohlmann T, Lopez-Lastra M, Darlix JL. Mechanism of HIV-1 Tat RNA translation and its activation by the Tat protein. Retrovirology. 2009 Aug 11;6:74. doi: 10.1186/1742-4690-6-74. PMID:19671151 doi:10.1186/1742-4690-6-74
- ↑ Peloponese JM Jr, Gregoire C, Opi S, Esquieu D, Sturgis J, Lebrun E, Meurs E, Collette Y, Olive D, Aubertin AM, Witvrow M, Pannecouque C, De Clercq E, Bailly C, Lebreton J, Loret EP. 1H-13C nuclear magnetic resonance assignment and structural characterization of HIV-1 Tat protein. C R Acad Sci III. 2000 Oct;323(10):883-94. PMID:11098404
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