Summary: Transactivating regulatory protein (Tat)
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Tat (HIV)". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at firstname.lastname@example.org and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Tat (HIV) Edit Wikipedia article
Bovine immunodeficiency virus tat–tar complex, nmr, 5 structures
Tat stands for "Trans-Activator of Transcription."The protein consists of between 86 and 101 amino acids depending on the subtype. 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, 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.
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.
By antagonizing the CXCR4 receptor, Tat also appears to selectively 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 after mutating from M-tropic strains.
Function and mechanism
Like other lentiviruses, HIV-1 encodes a trans-activating regulatory protein (Tat), which is essential for efficient transcription of the viral genome. 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 the positive transcription elongation complex (P-TEFb) of cellular CDK9 and cyclin T1, and hence increases the production of full-length viral RNA.
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.
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.
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.
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.
Protein transduction domain
Tat contains a protein transduction domain, and is therefore known as a cell-penetrating peptide. Originally characterised by Frankel and Pabo (1988) and Green and Loewenstein (1988), this domain allows Tat to enter cells by crossing the cell membrane. The amino acid sequence of the protein transduction domain is YGRKKRRQRRR. The nuclear localisation signal found within the domain, GRKKR, mediates further translocation of Tat into the cell nucleus. As of 2000[update] The biological role of this domain and exact mechanism of transfer is unknown.
- Genes, tat at the US National Library of Medicine Medical Subject Headings (MeSH)
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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. doi:10.1073/pnas.91.17.8248. PMC 44583. PMID 8058789.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. doi:10.4049/jimmunol.169.1.254. PMID 12077252.
- 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.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Transactivating regulatory protein (Tat) Provide feedback
The retroviral Tat protein binds to the Tar RNA . This activates transcriptional initiation and elongation from the LTR promoter. Binding is mediated by an arginine rich region.
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].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||host cell nucleus (GO:0042025)|
|Molecular function||sequence-specific DNA binding transcription factor activity (GO:0003700)|
|Biological process||regulation of transcription, DNA-templated (GO:0006355)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||2|
|Number in full:||10015|
|Average length of the domain:||60.40 aa|
|Average identity of full alignment:||70 %|
|Average coverage of the sequence by the domain:||69.80 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 22 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.
Loading structure mapping...