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| | ==Structural Characterization of a Complex Between the Acidic Transactivation Domain of EBNA2 and the Tfb1/p62 subunit of TFIIH.== | | ==Structural Characterization of a Complex Between the Acidic Transactivation Domain of EBNA2 and the Tfb1/p62 subunit of TFIIH.== |
| - | <StructureSection load='2mkr' size='340' side='right' caption='[[2mkr]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2mkr' size='340' side='right'caption='[[2mkr]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2mkr]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast] and [http://en.wikipedia.org/wiki/Ebvb9 Ebvb9]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MKR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MKR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2mkr]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast] and [https://en.wikipedia.org/wiki/Ebvb9 Ebvb9]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MKR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MKR FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">D9740.3, TFB1, YDR311W ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast]), BYRF1, EBNA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10377 EBVB9])</td></tr> | + | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">D9740.3, TFB1, YDR311W ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast]), BYRF1, EBNA2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10377 EBVB9])</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mkr OCA], [http://pdbe.org/2mkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mkr RCSB], [http://www.ebi.ac.uk/pdbsum/2mkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2mkr ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mkr OCA], [https://pdbe.org/2mkr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mkr RCSB], [https://www.ebi.ac.uk/pdbsum/2mkr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mkr ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TFB1_YEAST TFB1_YEAST]] Acts as component of the general transcription and DNA repair factor IIH (TFIIH) core, which is essential for both basal and activated transcription, and is involved in nucleotide excision repair (NER) of damaged DNA. TFIIH has CTD kinase and DNA-dependent ATPase activity, and is essential for polymerase II transcription in vitro.<ref>PMID:7961739</ref> <ref>PMID:8631896</ref> [[http://www.uniprot.org/uniprot/EBNA2_EBVB9 EBNA2_EBVB9]] Plays a key role in the activation of the host resting B-cell and stimulation of B-cell proliferation. Acts by up-regulating the expression of viral EBNA1-6, LMP1, LMP2A and LMP2B genes, as well as several host genes including CD21, CD23 and MYC. Activates transcription by acting as an adapter molecule that binds to cellular sequence-specific DNA-binding proteins such as host CBF1, SMARCB1 and SPI1. Once EBNA2 is near promoter sites, its acidic activating domain recruits basal and activation-associated transcription factors TFIIB, TAF40, TFIIH components ERCC2 and ERCC3, and CBP in order to promote transcription. Alternatively, EBNA2 can affect activities of cell cycle regulators and retard cell cycle progression at G2/M phase. It also induces chromosomal instability, by disrupting mitotic checkpoints, multi-nucleation and formation of micronuclei in infected cells.<ref>PMID:19126642</ref> | + | [[https://www.uniprot.org/uniprot/TFB1_YEAST TFB1_YEAST]] Acts as component of the general transcription and DNA repair factor IIH (TFIIH) core, which is essential for both basal and activated transcription, and is involved in nucleotide excision repair (NER) of damaged DNA. TFIIH has CTD kinase and DNA-dependent ATPase activity, and is essential for polymerase II transcription in vitro.<ref>PMID:7961739</ref> <ref>PMID:8631896</ref> [[https://www.uniprot.org/uniprot/EBNA2_EBVB9 EBNA2_EBVB9]] Plays a key role in the activation of the host resting B-cell and stimulation of B-cell proliferation. Acts by up-regulating the expression of viral EBNA1-6, LMP1, LMP2A and LMP2B genes, as well as several host genes including CD21, CD23 and MYC. Activates transcription by acting as an adapter molecule that binds to cellular sequence-specific DNA-binding proteins such as host CBF1, SMARCB1 and SPI1. Once EBNA2 is near promoter sites, its acidic activating domain recruits basal and activation-associated transcription factors TFIIB, TAF40, TFIIH components ERCC2 and ERCC3, and CBP in order to promote transcription. Alternatively, EBNA2 can affect activities of cell cycle regulators and retard cell cycle progression at G2/M phase. It also induces chromosomal instability, by disrupting mitotic checkpoints, multi-nucleation and formation of micronuclei in infected cells.<ref>PMID:19126642</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | [[Category: Baker's yeast]] | | [[Category: Baker's yeast]] |
| | [[Category: Ebvb9]] | | [[Category: Ebvb9]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Archambault, J]] | | [[Category: Archambault, J]] |
| | [[Category: Arseneault, G]] | | [[Category: Arseneault, G]] |
| Structural highlights
Function
[TFB1_YEAST] Acts as component of the general transcription and DNA repair factor IIH (TFIIH) core, which is essential for both basal and activated transcription, and is involved in nucleotide excision repair (NER) of damaged DNA. TFIIH has CTD kinase and DNA-dependent ATPase activity, and is essential for polymerase II transcription in vitro.[1] [2] [EBNA2_EBVB9] Plays a key role in the activation of the host resting B-cell and stimulation of B-cell proliferation. Acts by up-regulating the expression of viral EBNA1-6, LMP1, LMP2A and LMP2B genes, as well as several host genes including CD21, CD23 and MYC. Activates transcription by acting as an adapter molecule that binds to cellular sequence-specific DNA-binding proteins such as host CBF1, SMARCB1 and SPI1. Once EBNA2 is near promoter sites, its acidic activating domain recruits basal and activation-associated transcription factors TFIIB, TAF40, TFIIH components ERCC2 and ERCC3, and CBP in order to promote transcription. Alternatively, EBNA2 can affect activities of cell cycle regulators and retard cell cycle progression at G2/M phase. It also induces chromosomal instability, by disrupting mitotic checkpoints, multi-nucleation and formation of micronuclei in infected cells.[3]
Publication Abstract from PubMed
Infection with the Epstein-Barr virus (EBV) can lead to a number of human diseases including Hodgkin's and Burkitt's lymphomas. The development of these EBV-linked diseases is associated with the presence of nine viral latent proteins, including the nuclear antigen 2 (EBNA2). The EBNA2 protein plays a crucial role in EBV infection through its ability to activate transcription of both host and viral genes. As part of this function, EBNA2 associates with several host transcriptional regulatory proteins, including the Tfb1/p62 (yeast/human) subunit of the general transcription factor IIH (TFIIH) and the histone acetyltransferase CBP(CREB-binding protein)/p300, through interactions with its C-terminal transactivation domain (TAD). In this manuscript, we examine the interaction of the acidic TAD of EBNA2 (residues 431-487) with the Tfb1/p62 subunit of TFIIH and CBP/p300 using nuclear magnetic resonance (NMR) spectroscopy, isothermal titration calorimeter (ITC) and transactivation studies in yeast. NMR studies show that the TAD of EBNA2 binds to the pleckstrin homology (PH) domain of Tfb1 (Tfb1PH) and that residues 448-471 (EBNA2448-471) are necessary and sufficient for this interaction. NMR structural characterization of a Tfb1PH-EBNA2448-471 complex demonstrates that the intrinsically disordered TAD of EBNA2 forms a 9-residue alpha-helix in complex with Tfb1PH. Within this helix, three hydrophobic amino acids (Trp458, Ile461 and Phe462) make a series of important interactions with Tfb1PH and their importance is validated in ITC and transactivation studies using mutants of EBNA2. In addition, NMR studies indicate that the same region of EBNA2 is also required for binding to the KIX domain of CBP/p300. This study provides an atomic level description of interactions involving the TAD of EBNA2 with target host proteins. In addition, comparison of the Tfb1PH-EBNA2448-471 complex with structures of the TAD of p53 and VP16 bound to Tfb1PH highlights the versatility of intrinsically disordered acidic TADs in recognizing common target host proteins.
Structural and Functional Characterization of a Complex between the Acidic Transactivation Domain of EBNA2 and the Tfb1/p62 Subunit of TFIIH.,Chabot PR, Raiola L, Lussier-Price M, Morse T, Arseneault G, Archambault J, Omichinski JG PLoS Pathog. 2014 Mar 27;10(3):e1004042. doi: 10.1371/journal.ppat.1004042., eCollection 2014 Mar. PMID:24675874[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Svejstrup JQ, Feaver WJ, LaPointe J, Kornberg RD. RNA polymerase transcription factor IIH holoenzyme from yeast. J Biol Chem. 1994 Nov 11;269(45):28044-8. PMID:7961739
- ↑ Sung P, Guzder SN, Prakash L, Prakash S. Reconstitution of TFIIH and requirement of its DNA helicase subunits, Rad3 and Rad25, in the incision step of nucleotide excision repair. J Biol Chem. 1996 May 3;271(18):10821-6. PMID:8631896
- ↑ Pan SH, Tai CC, Lin CS, Hsu WB, Chou SF, Lai CC, Chen JY, Tien HF, Lee FY, Wang WB. Epstein-Barr virus nuclear antigen 2 disrupts mitotic checkpoint and causes chromosomal instability. Carcinogenesis. 2009 Feb;30(2):366-75. Epub 2009 Jan 6. PMID:19126642 doi:http://dx.doi.org/bgn291
- ↑ Chabot PR, Raiola L, Lussier-Price M, Morse T, Arseneault G, Archambault J, Omichinski JG. Structural and Functional Characterization of a Complex between the Acidic Transactivation Domain of EBNA2 and the Tfb1/p62 Subunit of TFIIH. PLoS Pathog. 2014 Mar 27;10(3):e1004042. doi: 10.1371/journal.ppat.1004042., eCollection 2014 Mar. PMID:24675874 doi:http://dx.doi.org/10.1371/journal.ppat.1004042
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