|
|
| Line 3: |
Line 3: |
| | <StructureSection load='1gh6' size='340' side='right'caption='[[1gh6]], [[Resolution|resolution]] 3.20Å' scene=''> | | <StructureSection load='1gh6' size='340' side='right'caption='[[1gh6]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1gh6]] is a 2 chain structure. The November 2003 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Simian Virus 40'' by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2003_11 10.2210/rcsb_pdb/mom_2003_11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GH6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1gh6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Macaca_mulatta_polyomavirus_1 Macaca mulatta polyomavirus 1]. The November 2003 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Simian Virus 40'' by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2003_11 10.2210/rcsb_pdb/mom_2003_11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GH6 FirstGlance]. <br> |
| - | </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=1gh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gh6 OCA], [https://pdbe.org/1gh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gh6 RCSB], [https://www.ebi.ac.uk/pdbsum/1gh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gh6 ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</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=1gh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gh6 OCA], [https://pdbe.org/1gh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gh6 RCSB], [https://www.ebi.ac.uk/pdbsum/1gh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gh6 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[https://www.uniprot.org/uniprot/RB_HUMAN RB_HUMAN]] Defects in RB1 are the cause of childhood cancer retinoblastoma (RB) [MIM:[https://omim.org/entry/180200 180200]]. RB is a congenital malignant tumor that arises from the nuclear layers of the retina. It occurs in about 1:20'000 live births and represents about 2% of childhood malignancies. It is bilateral in about 30% of cases. Although most RB appear sporadically, about 20% are transmitted as an autosomal dominant trait with incomplete penetrance. The diagnosis is usually made before the age of 2 years when strabismus or a gray to yellow reflex from pupil ('cat eye') is investigated.<ref>PMID:2594029</ref> <ref>PMID:1352883</ref> <ref>PMID:8346255</ref> <ref>PMID:7704558</ref> <ref>PMID:7927327</ref> <ref>PMID:8605116</ref> <ref>PMID:7795591</ref> <ref>PMID:8776589</ref> <ref>PMID:9311732</ref> <ref>PMID:9140452</ref> <ref>PMID:10671068</ref> <ref>PMID:9973307</ref> <ref>PMID:11524739</ref> Defects in RB1 are a cause of susceptibility to bladder cancer (BLC) [MIM:[https://omim.org/entry/109800 109800]]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Defects in RB1 are a cause of osteogenic sarcoma (OSRC) [MIM:[https://omim.org/entry/259500 259500]]. | |
| | == Function == | | == 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> [[https://www.uniprot.org/uniprot/RB_HUMAN RB_HUMAN]] Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, SUV420H1 and SUV420H2, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity). In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.<ref>PMID:15084261</ref>
| + | [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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 37: |
Line 36: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | + | [[Category: Macaca mulatta polyomavirus 1]] |
| | [[Category: RCSB PDB Molecule of the Month]] | | [[Category: RCSB PDB Molecule of the Month]] |
| | [[Category: Simian Virus 40]] | | [[Category: Simian Virus 40]] |
| - | [[Category: Cho, Y]] | + | [[Category: Cho Y]] |
| - | [[Category: Kim, H Y]] | + | [[Category: Kim HY]] |
| - | [[Category: Antitumor protein]]
| + | |
| - | [[Category: Oncoprotein]]
| + | |
| - | [[Category: Tumor suppressor]]
| + | |
| 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]
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
Inactivation of the retinoblastoma (Rb) tumor suppressor by Simian virus 40 (SV40) large T antigen is one of the central features of tumorigenesis induced by SV40. Both the N-terminal J domain and the LxCxE motif of large T antigen are required for inactivation of Rb. The crystal structure of the N-terminal region (residues 7-117) of SV40 large T antigen bound to the pocket domain of Rb reveals that large T antigen contains a four-helix bundle, and residues from helices alpha2 and alpha4 and from a loop containing the LxCxE motif participate in the interactions with Rb. The two central helices and a connecting loop in large T antigen have structural similarities with the J domains of the molecular chaperones DnaJ and HDJ-1, suggesting that large T antigen may use a chaperone mechanism for its biological function. However, there are significant differences between large T antigen and the molecular chaperones in other regions and these differences are likely to provide the specificity needed for large T antigen to inactivate Rb.
Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen.,Kim HY, Ahn BY, Cho Y EMBO J. 2001 Jan 15;20(1-2):295-304. PMID:11226179[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
- ↑ Kim HY, Ahn BY, Cho Y. Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen. EMBO J. 2001 Jan 15;20(1-2):295-304. PMID:11226179 doi:10.1093/emboj/20.1.295
|
