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| | ==NMR structure of the yeast Dun1 FHA domain in complex with a doubly phosphorylated (pT) peptide derived from Rad53 SCD1== | | ==NMR structure of the yeast Dun1 FHA domain in complex with a doubly phosphorylated (pT) peptide derived from Rad53 SCD1== |
| - | <StructureSection load='2jql' size='340' side='right'caption='[[2jql]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2jql' size='340' side='right'caption='[[2jql]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2jql]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JQL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2jql]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JQL FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2jqi|2jqi]], [[2jqj|2jqj]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DUN1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 Saccharomyces cerevisiae])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=2jql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jql OCA], [https://pdbe.org/2jql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jql RCSB], [https://www.ebi.ac.uk/pdbsum/2jql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jql 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=2jql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jql OCA], [https://pdbe.org/2jql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jql RCSB], [https://www.ebi.ac.uk/pdbsum/2jql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jql ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/DUN1_YEAST DUN1_YEAST]] Transducer of the DNA damage signal. Phosphorylates SML1 on serine residues. Cooperates with the PAN deadenylation complex in the regulation of RAD5 mRNA levels and cell survival in response to replicational stress.<ref>PMID:11953437</ref> <ref>PMID:11904430</ref> [[https://www.uniprot.org/uniprot/RAD53_YEAST RAD53_YEAST]] Controls S-phase checkpoint as well as G1 and G2 DNA damage checkpoints. Phosphorylates proteins on serine, threonine, and tyrosine. Prevents entry into anaphase and mitotic exit after DNA damage via regulation of the Polo kinase CDC5. Seems to be involved in the phosphorylation of RPH1.<ref>PMID:8355715</ref> <ref>PMID:7958905</ref> <ref>PMID:10550056</ref> <ref>PMID:11809875</ref> <ref>PMID:15024067</ref>
| + | [https://www.uniprot.org/uniprot/DUN1_YEAST DUN1_YEAST] Transducer of the DNA damage signal. Phosphorylates SML1 on serine residues. Cooperates with the PAN deadenylation complex in the regulation of RAD5 mRNA levels and cell survival in response to replicational stress.<ref>PMID:11953437</ref> <ref>PMID:11904430</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | |
| | [[Category: Saccharomyces cerevisiae]] | | [[Category: Saccharomyces cerevisiae]] |
| - | [[Category: Chang, C]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: Heierhorst, J]] | + | [[Category: Chang C]] |
| - | [[Category: Lee, H]] | + | [[Category: Heierhorst J]] |
| - | [[Category: Tsai, M]] | + | [[Category: Lee H]] |
| - | [[Category: Yuan, C]] | + | [[Category: Tsai M]] |
| - | [[Category: Cell cycle]]
| + | [[Category: Yuan C]] |
| - | [[Category: Protein/phosphopeptide]]
| + | |
| Structural highlights
Function
DUN1_YEAST Transducer of the DNA damage signal. Phosphorylates SML1 on serine residues. Cooperates with the PAN deadenylation complex in the regulation of RAD5 mRNA levels and cell survival in response to replicational stress.[1] [2]
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
Forkhead-associated (FHA) domains recognize phosphothreonines, and SQ/TQ cluster domains (SCDs) contain concentrated phosphorylation sites for ATM/ATR-like DNA-damage-response kinases. The Rad53-SCD1 has dual functions in regulating the activation of the Rad53-Dun1 checkpoint kinase cascade but with unknown molecular mechanisms. Here we present structural, biochemical, and genetic evidence that Dun1-FHA possesses an unprecedented diphosphothreonine-binding specificity. The Dun1-FHA has >100-fold increased affinity for diphosphorylated relative to monophosphorylated Rad53-SCD1 due to the presence of two separate phosphothreonine-binding pockets. In vivo, any single threonine of Rad53-SCD1 is sufficient for Rad53 activation and RAD53-dependent survival of DNA damage, but two adjacent phosphothreonines in the Rad53-SCD1 and two phosphothreonine-binding sites in the Dun1-FHA are necessary for Dun1 activation and DUN1-dependent transcriptional responses to DNA damage. The results uncover a phospho-counting mechanism that regulates the specificity of SCD, and provide mechanistic insight into a role of multisite phosphorylation in DNA-damage signaling.
Diphosphothreonine-specific interaction between an SQ/TQ cluster and an FHA domain in the Rad53-Dun1 kinase cascade.,Lee H, Yuan C, Hammet A, Mahajan A, Chen ES, Wu MR, Su MI, Heierhorst J, Tsai MD Mol Cell. 2008 Jun 20;30(6):767-78. PMID:18570878[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hammet A, Pike BL, Heierhorst J. Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2-Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. J Biol Chem. 2002 Jun 21;277(25):22469-74. Epub 2002 Apr 12. PMID:11953437 doi:http://dx.doi.org/10.1074/jbc.M202473200
- ↑ Zhao X, Rothstein R. The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3746-51. PMID:11904430 doi:http://dx.doi.org/10.1073/pnas.062502299
- ↑ Lee H, Yuan C, Hammet A, Mahajan A, Chen ES, Wu MR, Su MI, Heierhorst J, Tsai MD. Diphosphothreonine-specific interaction between an SQ/TQ cluster and an FHA domain in the Rad53-Dun1 kinase cascade. Mol Cell. 2008 Jun 20;30(6):767-78. PMID:18570878 doi:10.1016/j.molcel.2008.05.013
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