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- | [[Image:3qn2.png|left|200px]] | |
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- | <!--
| + | ==Structure-based design of a disulfide-linked oligomeric form of the Simian Virus 40 (SV40) large T antigen DNA binding domain== |
- | The line below this paragraph, containing "STRUCTURE_3qn2", creates the "Structure Box" on the page.
| + | <StructureSection load='3qn2' size='340' side='right'caption='[[3qn2]], [[Resolution|resolution]] 1.66Å' scene=''> |
- | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
- | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3qn2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Macaca_mulatta_polyomavirus_1 Macaca mulatta polyomavirus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QN2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QN2 FirstGlance]. <br> |
- | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.661Å</td></tr> |
- | --> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene></td></tr> |
- | {{STRUCTURE_3qn2| PDB=3qn2 | SCENE= }}
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qn2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qn2 OCA], [https://pdbe.org/3qn2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qn2 RCSB], [https://www.ebi.ac.uk/pdbsum/3qn2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qn2 ProSAT]</span></td></tr> |
| + | </table> |
| + | == Function == |
| + | [https://www.uniprot.org/uniprot/LT_SV40 LT_SV40] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.<ref>PMID:8647434</ref> <ref>PMID:9632777</ref> <ref>PMID:9488456</ref> <ref>PMID:15680424</ref> <ref>PMID:15611062</ref> <ref>PMID:17341466</ref> <ref>PMID:18922873</ref> Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.<ref>PMID:8647434</ref> <ref>PMID:9632777</ref> <ref>PMID:9488456</ref> <ref>PMID:15680424</ref> <ref>PMID:15611062</ref> <ref>PMID:17341466</ref> <ref>PMID:18922873</ref> |
| + | <div style="background-color:#fffaf0;"> |
| + | == Publication Abstract from PubMed == |
| + | The modular multifunctional protein large T antigen (T-ag) from simian virus 40 orchestrates many of the events needed for replication of the viral double-stranded DNA genome. This protein assembles into single and double hexamers on specific DNA sequences located at the origin of replication. This complicated process begins when the origin-binding domain of large T antigen (T-ag ODB) binds the GAGGC sequences in the central region (site II) of the viral origin of replication. While many of the functions of purified T-ag OBD can be studied in isolation, it is primarily monomeric in solution and cannot assemble into hexamers. To overcome this limitation, the possibility of engineering intermolecular disulfide bonds in the origin-binding domain which could oligomerize in solution was investigated. A recent crystal structure of the wild-type T-ag OBD showed that this domain forms a left-handed spiral in the crystal with six subunits per turn. Therefore, we analyzed the protein interface of this structure and identified two residues that could potentially support an intermolecular disulfide bond if changed to cysteines. SDS-PAGE analysis established that the mutant T-ag OBD formed higher oligomeric products in a redox-dependent manner. In addition, the 1.7 A resolution crystal structure of the engineered disulfide-linked T-ag OBD is reported, which establishes that oligomerization took place in the expected manner. |
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- | ===Structure-based design of a disulfide-linked oligomeric form of the Simian Virus 40 (SV40) large T antigen DNA binding domain===
| + | Structure-based design of a disulfide-linked oligomeric form of the simian virus 40 (SV40) large T antigen DNA-binding domain.,Meinke G, Phelan P, Fradet-Turcotte A, Archambault J, Bullock PA Acta Crystallogr D Biol Crystallogr. 2011 Jun;67(Pt 6):560-7. Epub 2011 May 17. PMID:21636896<ref>PMID:21636896</ref> |
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- | | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
- | <!--
| + | </div> |
- | The line below this paragraph, {{ABSTRACT_PUBMED_21636896}}, adds the Publication Abstract to the page
| + | <div class="pdbe-citations 3qn2" style="background-color:#fffaf0;"></div> |
- | (as it appears on PubMed at http://www.pubmed.gov), where 21636896 is the PubMed ID number.
| + | |
- | -->
| + | |
- | {{ABSTRACT_PUBMED_21636896}}
| + | |
- | | + | |
- | ==About this Structure== | + | |
- | [[3qn2]] is a 1 chain structure of [[Large T Antigen]] with sequence from [http://en.wikipedia.org/wiki/Simian_virus_40 Simian virus 40]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QN2 OCA].
| + | |
| | | |
| ==See Also== | | ==See Also== |
- | *[[Large T Antigen]] | + | *[[Large T Antigen|Large T Antigen]] |
- | | + | == References == |
- | ==Reference== | + | <references/> |
- | <ref group="xtra">PMID:021636896</ref><references group="xtra"/> | + | __TOC__ |
- | [[Category: Simian virus 40]] | + | </StructureSection> |
- | [[Category: Bullock, P A.]] | + | [[Category: Large Structures]] |
- | [[Category: Meinke, G.]] | + | [[Category: Macaca mulatta polyomavirus 1]] |
- | [[Category: Dna replication]] | + | [[Category: Bullock PA]] |
- | [[Category: Hydrolase]]
| + | [[Category: Meinke G]] |
- | [[Category: Origin binding domain]]
| + | |
| Structural highlights
Function
LT_SV40 Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.[1] [2] [3] [4] [5] [6] [7] Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.[8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
The modular multifunctional protein large T antigen (T-ag) from simian virus 40 orchestrates many of the events needed for replication of the viral double-stranded DNA genome. This protein assembles into single and double hexamers on specific DNA sequences located at the origin of replication. This complicated process begins when the origin-binding domain of large T antigen (T-ag ODB) binds the GAGGC sequences in the central region (site II) of the viral origin of replication. While many of the functions of purified T-ag OBD can be studied in isolation, it is primarily monomeric in solution and cannot assemble into hexamers. To overcome this limitation, the possibility of engineering intermolecular disulfide bonds in the origin-binding domain which could oligomerize in solution was investigated. A recent crystal structure of the wild-type T-ag OBD showed that this domain forms a left-handed spiral in the crystal with six subunits per turn. Therefore, we analyzed the protein interface of this structure and identified two residues that could potentially support an intermolecular disulfide bond if changed to cysteines. SDS-PAGE analysis established that the mutant T-ag OBD formed higher oligomeric products in a redox-dependent manner. In addition, the 1.7 A resolution crystal structure of the engineered disulfide-linked T-ag OBD is reported, which establishes that oligomerization took place in the expected manner.
Structure-based design of a disulfide-linked oligomeric form of the simian virus 40 (SV40) large T antigen DNA-binding domain.,Meinke G, Phelan P, Fradet-Turcotte A, Archambault J, Bullock PA Acta Crystallogr D Biol Crystallogr. 2011 Jun;67(Pt 6):560-7. Epub 2011 May 17. PMID:21636896[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Damania B, Alwine JC. TAF-like function of SV40 large T antigen. Genes Dev. 1996 Jun 1;10(11):1369-81. PMID:8647434
- ↑ Damania B, Lieberman P, Alwine JC. Simian virus 40 large T antigen stabilizes the TATA-binding protein-TFIIA complex on the TATA element. Mol Cell Biol. 1998 Jul;18(7):3926-35. PMID:9632777
- ↑ Zalvide J, Stubdal H, DeCaprio JA. The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins. Mol Cell Biol. 1998 Mar;18(3):1408-15. PMID:9488456
- ↑ Skoczylas C, Henglein B, Rundell K. PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. Virology. 2005 Feb 20;332(2):596-601. PMID:15680424 doi:10.1016/j.virol.2004.12.017
- ↑ Welcker M, Clurman BE. The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J Biol Chem. 2005 Mar 4;280(9):7654-8. Epub 2004 Dec 20. PMID:15611062 doi:10.1074/jbc.M413377200
- ↑ Valls E, Blanco-Garcia N, Aquizu N, Piedra D, Estaras C, de la Cruz X, Martinez-Balbas MA. Involvement of chromatin and histone deacetylation in SV40 T antigen transcription regulation. Nucleic Acids Res. 2007;35(6):1958-68. Epub 2007 Mar 6. PMID:17341466 doi:gkl1113
- ↑ Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J Virol. 2009 Jan;83(1):117-27. doi: 10.1128/JVI.01515-08. Epub 2008 Oct 15. PMID:18922873 doi:10.1128/JVI.01515-08
- ↑ Damania B, Alwine JC. TAF-like function of SV40 large T antigen. Genes Dev. 1996 Jun 1;10(11):1369-81. PMID:8647434
- ↑ Damania B, Lieberman P, Alwine JC. Simian virus 40 large T antigen stabilizes the TATA-binding protein-TFIIA complex on the TATA element. Mol Cell Biol. 1998 Jul;18(7):3926-35. PMID:9632777
- ↑ Zalvide J, Stubdal H, DeCaprio JA. The J domain of simian virus 40 large T antigen is required to functionally inactivate RB family proteins. Mol Cell Biol. 1998 Mar;18(3):1408-15. PMID:9488456
- ↑ Skoczylas C, Henglein B, Rundell K. PP2A-dependent transactivation of the cyclin A promoter by SV40 ST is mediated by a cell cycle-regulated E2F site. Virology. 2005 Feb 20;332(2):596-601. PMID:15680424 doi:10.1016/j.virol.2004.12.017
- ↑ Welcker M, Clurman BE. The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J Biol Chem. 2005 Mar 4;280(9):7654-8. Epub 2004 Dec 20. PMID:15611062 doi:10.1074/jbc.M413377200
- ↑ Valls E, Blanco-Garcia N, Aquizu N, Piedra D, Estaras C, de la Cruz X, Martinez-Balbas MA. Involvement of chromatin and histone deacetylation in SV40 T antigen transcription regulation. Nucleic Acids Res. 2007;35(6):1958-68. Epub 2007 Mar 6. PMID:17341466 doi:gkl1113
- ↑ Hein J, Boichuk S, Wu J, Cheng Y, Freire R, Jat PS, Roberts TM, Gjoerup OV. Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding. J Virol. 2009 Jan;83(1):117-27. doi: 10.1128/JVI.01515-08. Epub 2008 Oct 15. PMID:18922873 doi:10.1128/JVI.01515-08
- ↑ Meinke G, Phelan P, Fradet-Turcotte A, Archambault J, Bullock PA. Structure-based design of a disulfide-linked oligomeric form of the simian virus 40 (SV40) large T antigen DNA-binding domain. Acta Crystallogr D Biol Crystallogr. 2011 Jun;67(Pt 6):560-7. Epub 2011 May 17. PMID:21636896 doi:10.1107/S0907444911014302
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