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| | ==Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein== | | ==Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein== |
| - | <StructureSection load='1lgq' size='340' side='right' caption='[[1lgq]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='1lgq' size='340' side='right'caption='[[1lgq]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1lgq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LGQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1LGQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1lgq]] is a 2 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=1LGQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LGQ FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1lgp|1lgp]]</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]] 2.1Å</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=1lgq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lgq OCA], [http://pdbe.org/1lgq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1lgq RCSB], [http://www.ebi.ac.uk/pdbsum/1lgq PDBsum]</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=1lgq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lgq OCA], [https://pdbe.org/1lgq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1lgq RCSB], [https://www.ebi.ac.uk/pdbsum/1lgq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1lgq ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CHFR_HUMAN CHFR_HUMAN]] E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons. Acts in early prophase before chromosome condensation, when the centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the 'Lys-48'-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation, but are rather involved in signaling cellular stress.<ref>PMID:10935642</ref> <ref>PMID:11807090</ref> <ref>PMID:11912157</ref> <ref>PMID:14562038</ref> <ref>PMID:14694445</ref> <ref>PMID:18172500</ref> <ref>PMID:19182791</ref> | + | [https://www.uniprot.org/uniprot/CHFR_HUMAN CHFR_HUMAN] E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons. Acts in early prophase before chromosome condensation, when the centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the 'Lys-48'-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation, but are rather involved in signaling cellular stress.<ref>PMID:10935642</ref> <ref>PMID:11807090</ref> <ref>PMID:11912157</ref> <ref>PMID:14562038</ref> <ref>PMID:14694445</ref> <ref>PMID:18172500</ref> <ref>PMID:19182791</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lg/1lgq_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lg/1lgq_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </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/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </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=1lgq ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Halazonetis, T D]] | + | [[Category: Large Structures]] |
| - | [[Category: Huyen, Y]] | + | [[Category: Halazonetis TD]] |
| - | [[Category: Jeffrey, P D]] | + | [[Category: Huyen Y]] |
| - | [[Category: Loreto, I R]] | + | [[Category: Jeffrey PD]] |
| - | [[Category: Pavletich, N P]] | + | [[Category: Loreto IR]] |
| - | [[Category: Scolnick, D M]] | + | [[Category: Pavletich NP]] |
| - | [[Category: Stavridi, E S]] | + | [[Category: Scolnick DM]] |
| - | [[Category: Cell cycle]]
| + | [[Category: Stavridi ES]] |
| - | [[Category: Checkpoint]]
| + | |
| - | [[Category: Chfr]]
| + | |
| - | [[Category: Domain swapping]]
| + | |
| - | [[Category: Fha]]
| + | |
| Structural highlights
Function
CHFR_HUMAN E3 ubiquitin-protein ligase that functions in the antephase checkpoint by actively delaying passage into mitosis in response to microtubule poisons. Acts in early prophase before chromosome condensation, when the centrosome move apart from each other along the periphery of the nucleus. Probably involved in signaling the presence of mitotic stress caused by microtubule poisons by mediating the 'Lys-48'-linked ubiquitination of target proteins, leading to their degradation by the proteasome. Promotes the ubiquitination and subsequent degradation of AURKA and PLK1. Probably acts as a tumor suppressor, possibly by mediating the polyubiquitination of HDAC1, leading to its degradation. May also promote the formation of 'Lys-63'-linked polyubiquitin chains and functions with the specific ubiquitin-conjugating UBC13-MMS2 (UBE2N-UBE2V2) heterodimer. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation, but are rather involved in signaling cellular stress.[1] [2] [3] [4] [5] [6] [7]
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 Chfr mitotic checkpoint protein is frequently inactivated in human cancer. We determined the three-dimensional structure of its FHA domain in its native form and in complex with tungstate, an analog of phosphate. The structures revealed a beta sandwich fold similar to the previously determined folds of the Rad53 N- and C-terminal FHA domains, except that the Rad53 domains were monomeric, whereas the Chfr FHA domain crystallized as a segment-swapped dimer. The ability of the Chfr FHA domain to recognize tungstate suggests that it shares the ability with other FHA domains to bind phosphoproteins. Nevertheless, differences in the sequence and structure of the Chfr and Rad53 FHA domains suggest that FHA domains can be divided into families with distinct binding properties.
Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate.,Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis TD, Pavletich NP, Jeffrey PD Structure. 2002 Jul;10(7):891-9. PMID:12121644[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Scolnick DM, Halazonetis TD. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature. 2000 Jul 27;406(6794):430-5. PMID:10935642 doi:10.1038/35019108
- ↑ Kang D, Chen J, Wong J, Fang G. The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition. J Cell Biol. 2002 Jan 21;156(2):249-59. Epub 2002 Jan 21. PMID:11807090 doi:10.1083/jcb.200108016
- ↑ Chaturvedi P, Sudakin V, Bobiak ML, Fisher PW, Mattern MR, Jablonski SA, Hurle MR, Zhu Y, Yen TJ, Zhou BB. Chfr regulates a mitotic stress pathway through its RING-finger domain with ubiquitin ligase activity. Cancer Res. 2002 Mar 15;62(6):1797-801. PMID:11912157
- ↑ Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD. The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains. Oncogene. 2003 Oct 16;22(46):7101-7. PMID:14562038 doi:10.1038/sj.onc.1206831
- ↑ Erson AE, Petty EM. CHFR-associated early G2/M checkpoint defects in breast cancer cells. Mol Carcinog. 2004 Jan;39(1):26-33. PMID:14694445 doi:10.1002/mc.10161
- ↑ Ahel I, Ahel D, Matsusaka T, Clark AJ, Pines J, Boulton SJ, West SC. Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature. 2008 Jan 3;451(7174):81-5. doi: 10.1038/nature06420. PMID:18172500 doi:10.1038/nature06420
- ↑ Oh YM, Kwon YE, Kim JM, Bae SJ, Lee BK, Yoo SJ, Chung CH, Deshaies RJ, Seol JH. Chfr is linked to tumour metastasis through the downregulation of HDAC1. Nat Cell Biol. 2009 Mar;11(3):295-302. doi: 10.1038/ncb1837. Epub 2009 Feb 1. PMID:19182791 doi:10.1038/ncb1837
- ↑ Stavridi ES, Huyen Y, Loreto IR, Scolnick DM, Halazonetis TD, Pavletich NP, Jeffrey PD. Crystal structure of the FHA domain of the Chfr mitotic checkpoint protein and its complex with tungstate. Structure. 2002 Jul;10(7):891-9. PMID:12121644
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