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16  structures 90  species 0  interactions 7178  sequences 3  architectures

Family: Tat (PF00539)

Summary: Transactivating regulatory protein (Tat)

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Tat (HIV) Edit Wikipedia article

Tat
PDB 1biv EBI.jpg
Bovine immunodeficiency virus tat–tar complex, nmr, 5 structures
Identifiers
Symbol Tat
Pfam PF00539
InterPro IPR001831
PROSITE PDOC00836
SCOP 1tvs
SUPERFAMILY 1tvs
TCDB 2.A.64

tat is an HIV gene.[1][2]

Tat stands for "Trans-Activator of Transcription". Tat consists of between 86 and 101 amino acids depending on the subtype.[3]

Also, in molecular biology, tat is a protein which is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription.[4]

Function[edit]

Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes,[5] providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

Tat also appears to play a more direct role in the HIV disease process. The protein is released by infected cells in culture, and is found in the blood of HIV-1 infected patients.[6]

It can be absorbed by cells that are not infected with HIV, and can act directly as a toxin producing cell death via apoptosis in uninfected "bystander" T cells, assisting in progression toward AIDS.[7]

By interacting with the CXCR4 receptor, Tat also appears to encourage the reproduction of less virulent M-tropic (macrophage-tropic) strains of HIV (which use the CCR5 receptor) early in the course of infection, allowing the more rapidly pathogenic T-tropic (T-cell-tropic) strains (which use the CXCR4 receptor) to emerge later.[6]

Function and mechanism[edit]

Like other lentiviruses, HIV-1 encodes a trans-activating regulatory protein (Tat), which is essential for efficient transcription of the viral genome.[8][9] Tat acts by binding to an RNA stem-loop structure, the trans-activating response element (TAR), found at the 5′ ends of nascent HIV-1 transcripts. In binding to TAR, Tat alters the properties of the transcription complex, recruits a positive transcription elongation complex (P-TEFb) and hence increases the production of full-length viral RNA.[9] Tat protein also associates with RNA polymerase II complexes during early transcription elongation after the promoter clearance and before the synthesis of full-length TAR RNA transcript. This interaction of Tat with RNA polymerase II elongation complexes is P-TEFb-independent. There are two Tat binding sites on each transcription elongation complex; one is located on TAR RNA and the other one on RNA polymerase II near the exit site for nascent mRNA transcripts which suggests that two Tat molecules are involved in performing various functions during a single round of HIV-1 mRNA synthesis.[10]

The minimum Tat sequence that can mediate specific TAR binding in vitro has been mapped to a basic domain of 10 amino acids, comprising mostly Arg and Lys residues. Regulatory activity, however, also requires the 47 N-terminal residues, which interact with components of the transcription complex and function as a transcriptional activation domain.[9][11][12]

Tat also uses an unusual transcellular transport pathway. Firstly, it binds with high affinity to phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2), found on the inner surface of the cell membrane, this enables Tat recruitment at this level. Tat then crosses the plasma membrane to reach the extracellular space. Tat secretion by infected cells is highly active, and export is the major destination for HIV-1 Tat.[4]

Structure[edit]

The basic region of HIV-Tat protein is suggested to form an alpha helix. The basic region is involved in RNA (TAR, trans-activation response element) binding and Tat proteins thus belong to the family of arginine-rich motif (ARM) RNA binding proteins.[13]

Protein transduction domain[edit]

Tat contains a protein transduction domain, and is therefore known as a cell-penetrating peptide.[14] Originally[15] characterised by Frankel and Pabo (1988)[16] and Green and Loewenstein (1988),[17] this domain allows Tat to enter cells by crossing the cell membrane. The amino acid sequence of the protein transduction domain is YGRKKRRQRRR.[14] The nuclear localisation signal found within the domain, GRKKR, mediates further translocation of Tat into the cell nucleus.[18][19] As of 2000 The biological role of this domain and exact mechanism of transfer is unknown.[14]

Clinical significance[edit]

Inhibition of Tat has been investigated.[20] It has been suggested that Tat antagonists may be of use in the treatment of HIV infections.[21]

References[edit]

  1. ^ tat Gene Products, Human Immunodeficiency Virus at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. ^ Genes, tat at the US National Library of Medicine Medical Subject Headings (MeSH)
  3. ^ Jeang, K. T. (1996) In: Human Retroviruses and AIDS: "A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences". Los Alamos National Laboratory (Ed.) pp. III-3–III-18
  4. ^ a b Debaisieux S, Rayne F, Yezid H, Beaumelle B (2012). "The ins and outs of HIV-1 Tat.". Traffic 13 (3): 355–63. doi:10.1111/j.1600-0854.2011.01286.x. PMID 21951552. 
  5. ^ Kim JB, Sharp PA (April 2001). "Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase". J. Biol. Chem. 276 (15): 12317–23. doi:10.1074/jbc.M010908200. PMID 11145967. 
  6. ^ a b Xiao H, Neuveut C, Tiffany HL, et al. (October 2000). "Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1". Proc. Natl. Acad. Sci. U.S.A. 97 (21): 11466–71. doi:10.1073/pnas.97.21.11466. PMC 17223. PMID 11027346. 
  7. ^ Campbell GR, Pasquier E, Watkins J, Bourgarel-Rey V, Peyrot V, Esquieu D, Barbier P, de Mareuil J, Braguer D, Kaleebu P, Yirrell DL, Loret EP (November 2004). "The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis". J. Biol. Chem. 279 (46): 48197–204. doi:10.1074/jbc.M406195200. PMID 15331610. 
  8. ^ Vaishnav YN, Wong-Staal F (1991). "The biochemistry of AIDS". Annu. Rev. Biochem. 60: 577–630. doi:10.1146/annurev.bi.60.070191.003045. PMID 1883204. 
  9. ^ a b c Mujeeb A, Bishop K, Peterlin BM, Turck C, Parslow TG, James TL (August 1994). "NMR structure of a biologically active peptide containing the RNA-binding domain of human immunodeficiency virus type 1 Tat". Proc. Natl. Acad. Sci. U.S.A. 91 (17): 8248–52. PMC 44583. PMID 8058789. 
  10. ^ Zhou C, Rana TM (July 2002). "A bimolecular mechanism of HIV-1 Tat protein interaction with RNA polymerase II transcription elongation complexes". J. Mol. Biol. 320 (5): 925–42. doi:10.1016/S0022-2836(02)00556-9. PMID 12126615. 
  11. ^ Selby MJ, Peterlin BM (August 1990). "Trans-activation by HIV-1 Tat via a heterologous RNA binding protein". Cell 62 (4): 769–76. doi:10.1016/0092-8674(90)90121-T. PMID 2117500. 
  12. ^ Kashanchi F, Piras G, Radonovich MF, Duvall JF, Fattaey A, Chiang CM, Roeder RG, Brady JN (January 1994). "Direct interaction of human TFIID with the HIV-1 transactivator Tat". Nature 367 (6460): 295–9. doi:10.1038/367295a0. PMID 8121496. 
  13. ^ Tahirov TH, Babayeva ND, Varzavand K, Cooper JJ, Sedore SC, Price DH (June 2010). "Crystal structure of HIV-1 Tat complexed with human P-TEFb". Nature 465 (7299): 747–51. doi:10.1038/nature09131. PMC 2885016. PMID 20535204. 
  14. ^ a b c Schwarze SR, Hruska KA, Dowdy SF (July 2000). "Protein transduction: unrestricted delivery into all cells?". Trends Cell Biol. 10 (7): 290–5. doi:10.1016/S0962-8924(00)01771-2. PMID 10856932. 
  15. ^ Dietz GP, Bähr M (October 2004). "Delivery of bioactive molecules into the cell: the Trojan horse approach". Molecular and Cellular Neuroscience 27 (2): 85–131. doi:10.1016/j.mcn.2004.03.005. PMID 15485768. 
  16. ^ Frankel AD, Pabo CO (December 1988). "Cellular uptake of the tat protein from human immunodeficiency virus". Cell 55 (6): 1189–93. doi:10.1016/0092-8674(88)90263-2. PMID 2849510. 
  17. ^ Green M, Loewenstein PM (December 1988). "Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein". Cell 55 (6): 1179–88. doi:10.1016/0092-8674(88)90262-0. PMID 2849509. 
  18. ^ Ruben S, Perkins A, Purcell R, et al. (January 1989). "Structural and functional characterization of human immunodeficiency virus Tat protein". Journal of Virology 63 (1): 1–8. PMC 247650. PMID 2535718. 
  19. ^ Hauber J, Malim MH, Cullen BR (March 1989). "Mutational analysis of the conserved basic domain of human immunodeficiency virus tat protein". Journal of Virology 63 (3): 1181–7. PMC 247813. PMID 2536828. 
  20. ^ Cook JA, August A, Henderson AJ (July 2002). "Recruitment of phosphatidylinositol 3-kinase to CD28 inhibits HIV transcription by a Tat-dependent mechanism". J. Immunol. 169 (1): 254–60. PMID 12077252. 
  21. ^ Bedoya LM, Beltrán M, Sancho R, et al. (October 2005). "4-Phenylcoumarins as HIV transcription inhibitors". Bioorg. Med. Chem. Lett. 15 (20): 4447–50. doi:10.1016/j.bmcl.2005.07.041. PMID 16137881. 

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Transactivating regulatory protein (Tat) Provide feedback

The retroviral Tat protein binds to the Tar RNA [4]. This activates transcriptional initiation and elongation from the LTR promoter. Binding is mediated by an arginine rich region.

Literature references

  1. Willbold D, Rosin-Arbesfeld R, Sticht H, Frank R, Rosch P; , Science 1994;264:1584-1587.: Structure of the equine infectious anemia virus Tat protein. PUBMED:7515512 EPMC:7515512

  2. Puglisi JD, Chen L, Blanchard S, Frankel AD; , Science 1995;270:1200-1203.: Solution structure of a bovine immunodeficiency virus Tat-TAR peptide-RNA complex. PUBMED:7502045 EPMC:7502045

  3. Brodsky AS, Williamson JR; , J Mol Biol 1997;267:624-639.: Solution structure of the HIV-2 TAR-argininamide complex. PUBMED:9126842 EPMC:9126842

  4. Berkhout B, Silverman RH, Jeang KT; , Cell 1989;59:273-282.: Tat trans-activates the human immunodeficiency virus through a nascent RNA target. PUBMED:2478293 EPMC:2478293

  5. Jeang KT, Xiao H, Rich EA; , J Biol Chem 1999;274:28837-28840.: Multifaceted activities of the HIV-1 transactivator of transcription, Tat. PUBMED:10506122 EPMC:10506122


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001831

Like other lentiviruses, Human immunodeficiency virus 1 (HIV-1) encodes a trans-activating regulatory protein (Tat), which is essential for efficient transcription of the viral genome [PUBMED:1883204, PUBMED:8058789]. Tat acts by binding to an RNA stem-loop structure, the trans-activating response element (TAR), found at the 5' ends of nascent HIV-1 transcripts. In binding to TAR, Tat alters the properties of the transcription complex, recruits a positive transcription elongation complex (P-TEFb) and hence increases the production of full-length viral RNA [PUBMED:8058789]. Tat protein also associates with RNA polymerase II complexes during early transcription elongation after the promoter clearance and before the synthesis of full-length TAR RNA transcript. This interaction of Tat with RNA polymerase II elongation complexes is P-TEFb-independent. There are two Tat binding sites on each transcription elongation complex; one is located on TAR RNA and the other one on RNA polymerase II near the exit site for nascent mRNA transcripts which suggests that two Tat molecules are involved in performing various functions during a single round of HIV-1 mRNA synthesis [PUBMED:12126615].

The minimum Tat sequence that can mediate specific TAR binding in vitro has been mapped to a basic domain of 10 amino acids, comprising mostly Arg and Lys residues. Regulatory activity, however, also requires the 47 N-terminal residues, which interact with components of the transcription complex and function as a transcriptional activation domain [PUBMED:8058789, PUBMED:2117500, PUBMED:8121496].

Gene Ontology

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Domain organisation

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Curation and family details

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Seed source: SCOP
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 83
Number in full: 7178
Average length of the domain: 64.90 aa
Average identity of full alignment: 66 %
Average coverage of the sequence by the domain: 73.19 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.5 22.5
Trusted cut-off 22.5 22.5
Noise cut-off 22.4 22.4
Model length: 68
Family (HMM) version: 13
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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Tat domain has been found. There are 16 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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