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| - | {{STRUCTURE_2qdj| PDB=2qdj | SCENE= }} | |
| - | ===Crystal structure of the Retinoblastoma protein N-domain provides insight into tumor suppression, ligand interaction and holoprotein architecture=== | |
| - | {{ABSTRACT_PUBMED_17996702}} | |
| | | | |
| - | ==Disease== | + | ==Crystal structure of the Retinoblastoma protein N-domain provides insight into tumor suppression, ligand interaction and holoprotein architecture== |
| - | [[http://www.uniprot.org/uniprot/RB_HUMAN RB_HUMAN]] Defects in RB1 are the cause of childhood cancer retinoblastoma (RB) [MIM:[http://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:[http://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:[http://omim.org/entry/259500 259500]]. | + | <StructureSection load='2qdj' size='340' side='right'caption='[[2qdj]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2qdj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QDJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QDJ FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></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=2qdj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qdj OCA], [https://pdbe.org/2qdj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qdj RCSB], [https://www.ebi.ac.uk/pdbsum/2qdj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qdj ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qd/2qdj_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2qdj ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The retinoblastoma susceptibility protein, Rb, has a key role in regulating cell-cycle progression via interactions involving the central "pocket" and C-terminal regions. While the N-terminal domain of Rb is dispensable for this function, it is nonetheless strongly conserved and harbors missense mutations found in hereditary retinoblastoma, indicating that disruption of its function is oncogenic. The crystal structure of the Rb N-terminal domain (RbN), reveals a globular entity formed by two rigidly connected cyclin-like folds. The similarity of RbN to the A and B boxes of the Rb pocket domain suggests that Rb evolved through domain duplication. Structural and functional analysis provides insight into oncogenicity of mutations in RbN and identifies a unique phosphorylation-regulated site of protein interaction. Additionally, this analysis suggests a coherent conformation for the Rb holoprotein in which RbN and pocket domains directly interact, and which can be modulated through ligand binding and possibly Rb phosphorylation. |
| | | | |
| - | ==Function==
| + | Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture.,Hassler M, Singh S, Yue WW, Luczynski M, Lakbir R, Sanchez-Sanchez F, Bader T, Pearl LH, Mittnacht S Mol Cell. 2007 Nov 9;28(3):371-85. PMID:17996702<ref>PMID:17996702</ref> |
| - | [[http://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>
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | [[2qdj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QDJ OCA].
| + | </div> |
| | + | <div class="pdbe-citations 2qdj" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Retinoblastoma protein|Retinoblastoma protein]] | | *[[Retinoblastoma protein|Retinoblastoma protein]] |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | <ref group="xtra">PMID:017996702</ref><references group="xtra"/><references/>
| + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Hassler, M.]] | + | [[Category: Large Structures]] |
| - | [[Category: Mittnacht, S.]] | + | [[Category: Hassler M]] |
| - | [[Category: Pearl, L H.]] | + | [[Category: Mittnacht S]] |
| - | [[Category: Antitumor protein]] | + | [[Category: Pearl LH]] |
| - | [[Category: Cyclin fold]]
| + | |
| - | [[Category: Cyclin wedge]]
| + | |
| Structural highlights
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
The retinoblastoma susceptibility protein, Rb, has a key role in regulating cell-cycle progression via interactions involving the central "pocket" and C-terminal regions. While the N-terminal domain of Rb is dispensable for this function, it is nonetheless strongly conserved and harbors missense mutations found in hereditary retinoblastoma, indicating that disruption of its function is oncogenic. The crystal structure of the Rb N-terminal domain (RbN), reveals a globular entity formed by two rigidly connected cyclin-like folds. The similarity of RbN to the A and B boxes of the Rb pocket domain suggests that Rb evolved through domain duplication. Structural and functional analysis provides insight into oncogenicity of mutations in RbN and identifies a unique phosphorylation-regulated site of protein interaction. Additionally, this analysis suggests a coherent conformation for the Rb holoprotein in which RbN and pocket domains directly interact, and which can be modulated through ligand binding and possibly Rb phosphorylation.
Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture.,Hassler M, Singh S, Yue WW, Luczynski M, Lakbir R, Sanchez-Sanchez F, Bader T, Pearl LH, Mittnacht S Mol Cell. 2007 Nov 9;28(3):371-85. PMID:17996702[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hassler M, Singh S, Yue WW, Luczynski M, Lakbir R, Sanchez-Sanchez F, Bader T, Pearl LH, Mittnacht S. Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell. 2007 Nov 9;28(3):371-85. PMID:17996702 doi:10.1016/j.molcel.2007.08.023
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