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| | ==Crystal Structure of the Papillomavirus DNA Tethering Complex E2:Brd4== | | ==Crystal Structure of the Papillomavirus DNA Tethering Complex E2:Brd4== |
| - | <StructureSection load='2nnu' size='340' side='right' caption='[[2nnu]], [[Resolution|resolution]] 1.59Å' scene=''> | + | <StructureSection load='2nnu' size='340' side='right'caption='[[2nnu]], [[Resolution|resolution]] 1.59Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2nnu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hpv16 Hpv16] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NNU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2NNU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2nnu]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hpv16 Hpv16] and [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NNU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NNU FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">E2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=333760 HPV16]), BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">E2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=333760 HPV16]), BRD4, HUNK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2nnu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nnu OCA], [http://pdbe.org/2nnu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2nnu RCSB], [http://www.ebi.ac.uk/pdbsum/2nnu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2nnu 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=2nnu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nnu OCA], [https://pdbe.org/2nnu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2nnu RCSB], [https://www.ebi.ac.uk/pdbsum/2nnu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2nnu ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref> | + | [[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VE2_HPV16 VE2_HPV16]] Plays an accessory role in initiation of DNA replication. A dimer of E2 interacts with a dimer of E1 in order to improve specificity of E1 DNA binding activity. Once the complex recognizes and binds DNA at specific sites, the E2 dimer is removed from DNA. E2 also regulates viral transcription through binding to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory regions of the viral genome. Activates or represses transcription depending on E2RE's position with regards to proximal promoter elements including the TATA-box. Repression occurs by sterically hindering the assembly of the transcription initiation complex.<ref>PMID:3033289</ref> <ref>PMID:1326651</ref> <ref>PMID:15681049</ref> [[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | + | [[https://www.uniprot.org/uniprot/VE2_HPV16 VE2_HPV16]] Plays an accessory role in initiation of DNA replication. A dimer of E2 interacts with a dimer of E1 in order to improve specificity of E1 DNA binding activity. Once the complex recognizes and binds DNA at specific sites, the E2 dimer is removed from DNA. E2 also regulates viral transcription through binding to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory regions of the viral genome. Activates or represses transcription depending on E2RE's position with regards to proximal promoter elements including the TATA-box. Repression occurs by sterically hindering the assembly of the transcription initiation complex.<ref>PMID:3033289</ref> <ref>PMID:1326651</ref> <ref>PMID:15681049</ref> [[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </div> | | </div> |
| | <div class="pdbe-citations 2nnu" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 2nnu" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Regulatory protein E2|Regulatory protein E2]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | [[Category: Hpv16]] | | [[Category: Hpv16]] |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Abbate, E A]] | | [[Category: Abbate, E A]] |
| | [[Category: Botchan, M R]] | | [[Category: Botchan, M R]] |
| Structural highlights
Disease
[BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2]
Function
[VE2_HPV16] Plays an accessory role in initiation of DNA replication. A dimer of E2 interacts with a dimer of E1 in order to improve specificity of E1 DNA binding activity. Once the complex recognizes and binds DNA at specific sites, the E2 dimer is removed from DNA. E2 also regulates viral transcription through binding to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory regions of the viral genome. Activates or represses transcription depending on E2RE's position with regards to proximal promoter elements including the TATA-box. Repression occurs by sterically hindering the assembly of the transcription initiation complex.[3] [4] [5] [BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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
Many DNA viruses that are latent in dividing cells are noncovalent passengers on mitotic chromosomes and require specific viral-encoded and cellular factors for this activity. The chromosomal protein Brd4 is implicated in the hitchhiking of bovine papillomavirus-1 (BPV-1), and the viral protein E2 binds to both plasmids and Brd4. Here, we present the X-ray crystal structure of the carboxy-terminal domain of Brd4 in complex with HPV-16 E2, and with this information have developed a Brd4-Tat fusion protein that is efficiently taken up by different transformed cells harboring HPV plasmids. In cells treated with these fusion proteins for only 2 hr and arrested in metaphase, the HPV DNA, either HPV-16 or -31, is displaced from mitotic chromosomes. Mutant Brd4 peptides are deficient in ablating this association. We suggest that such peptides may lead to the development of inhibitors of latency for many, if not all, papillomaviruses.
Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association.,Abbate EA, Voitenleitner C, Botchan MR Mol Cell. 2006 Dec 28;24(6):877-89. PMID:17189190[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
- ↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
- ↑ Phelps WC, Howley PM. Transcriptional trans-activation by the human papillomavirus type 16 E2 gene product. J Virol. 1987 May;61(5):1630-8. PMID:3033289
- ↑ Del Vecchio AM, Romanczuk H, Howley PM, Baker CC. Transient replication of human papillomavirus DNAs. J Virol. 1992 Oct;66(10):5949-58. PMID:1326651
- ↑ Okoye A, Cordano P, Taylor ER, Morgan IM, Everett R, Campo MS. Human papillomavirus 16 L2 inhibits the transcriptional activation function, but not the DNA replication function, of HPV-16 E2. Virus Res. 2005 Mar;108(1-2):1-14. PMID:15681049 doi:10.1016/j.virusres.2004.07.004
- ↑ Abbate EA, Voitenleitner C, Botchan MR. Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association. Mol Cell. 2006 Dec 28;24(6):877-89. PMID:17189190 doi:10.1016/j.molcel.2006.11.002
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