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| | <StructureSection load='5mkw' size='340' side='right'caption='[[5mkw]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='5mkw' size='340' side='right'caption='[[5mkw]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mkw]] 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=5MKW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MKW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mkw]] 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=5MKW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MKW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ZRANB3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5mkw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkw OCA], [http://pdbe.org/5mkw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mkw RCSB], [http://www.ebi.ac.uk/pdbsum/5mkw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkw 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=5mkw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkw OCA], [https://pdbe.org/5mkw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mkw RCSB], [https://www.ebi.ac.uk/pdbsum/5mkw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkw ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ZRAB3_HUMAN ZRAB3_HUMAN]] DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events. Recruited to the sites of stalled DNA replication by polyubiquitinated PCNA and acts as a structure-specific endonuclease that cleaves the replication fork D-loop intermediate, generating an accessible 3'-OH group in the template of the leading strand, which is amenable to extension by DNA polymerase. In addition to endonuclease activity, also catalyzes the fork regression via annealing helicase activity in order to prevent disintegration of the replication fork and the formation of double-strand breaks.<ref>PMID:21078962</ref> <ref>PMID:22704558</ref> <ref>PMID:22705370</ref> <ref>PMID:22759634</ref> <ref>PMID:26884333</ref> | + | [https://www.uniprot.org/uniprot/ZRAB3_HUMAN ZRAB3_HUMAN] DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events. Recruited to the sites of stalled DNA replication by polyubiquitinated PCNA and acts as a structure-specific endonuclease that cleaves the replication fork D-loop intermediate, generating an accessible 3'-OH group in the template of the leading strand, which is amenable to extension by DNA polymerase. In addition to endonuclease activity, also catalyzes the fork regression via annealing helicase activity in order to prevent disintegration of the replication fork and the formation of double-strand breaks.<ref>PMID:21078962</ref> <ref>PMID:22704558</ref> <ref>PMID:22705370</ref> <ref>PMID:22759634</ref> <ref>PMID:26884333</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ariza, A]] | + | [[Category: Ariza A]] |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Endonuclease]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Metalloprotein]]
| + | |
| - | [[Category: Zinc-binding]]
| + | |
| Structural highlights
Function
ZRAB3_HUMAN DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events. Recruited to the sites of stalled DNA replication by polyubiquitinated PCNA and acts as a structure-specific endonuclease that cleaves the replication fork D-loop intermediate, generating an accessible 3'-OH group in the template of the leading strand, which is amenable to extension by DNA polymerase. In addition to endonuclease activity, also catalyzes the fork regression via annealing helicase activity in order to prevent disintegration of the replication fork and the formation of double-strand breaks.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Strategies to resolve replication blocks are critical for the maintenance of genome stability. Among the factors implicated in the replication stress response is the ATP-dependent endonuclease ZRANB3. Here, we present the structure of the ZRANB3 HNH (His-Asn-His) endonuclease domain and provide a detailed analysis of its activity. We further define PCNA as a key regulator of ZRANB3 function, which recruits ZRANB3 to stalled replication forks and stimulates its endonuclease activity. Finally, we present the co-crystal structures of PCNA with two specific motifs in ZRANB3: the PIP box and the APIM motif. Our data provide important structural insights into the PCNA-APIM interaction, and reveal unexpected similarities between the PIP box and the APIM motif. We propose that PCNA and ATP-dependency serve as a multi-layered regulatory mechanism that modulates ZRANB3 activity at replication forks. Importantly, our findings allow us to interpret the functional significance of cancer associated ZRANB3 mutations.
Structural insights into the function of ZRANB3 in replication stress response.,Sebesta M, Cooper CDO, Ariza A, Carnie CJ, Ahel D Nat Commun. 2017 Jun 16;8:15847. doi: 10.1038/ncomms15847. PMID:28621305[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yusufzai T, Kadonaga JT. Annealing helicase 2 (AH2), a DNA-rewinding motor with an HNH motif. Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20970-3. Epub 2010 Nov 15. PMID:21078962 doi:10.1073/pnas.1011196107
- ↑ Ciccia A, Nimonkar AV, Hu Y, Hajdu I, Achar YJ, Izhar L, Petit SA, Adamson B, Yoon JC, Kowalczykowski SC, Livingston DM, Haracska L, Elledge SJ. Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol Cell. 2012 Aug 10;47(3):396-409. doi: 10.1016/j.molcel.2012.05.024. Epub 2012, Jun 14. PMID:22704558 doi:http://dx.doi.org/10.1016/j.molcel.2012.05.024
- ↑ Yuan J, Ghosal G, Chen J. The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. Mol Cell. 2012 Aug 10;47(3):410-21. doi: 10.1016/j.molcel.2012.05.025. Epub 2012 , Jun 14. PMID:22705370 doi:http://dx.doi.org/10.1016/j.molcel.2012.05.025
- ↑ Weston R, Peeters H, Ahel D. ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response. Genes Dev. 2012 Jul 15;26(14):1558-72. doi: 10.1101/gad.193516.112. Epub 2012 Jul, 3. PMID:22759634 doi:http://dx.doi.org/10.1101/gad.193516.112
- ↑ Badu-Nkansah A, Mason AC, Eichman BF, Cortez D. Identification of a Substrate Recognition Domain in the Replication Stress Response Protein Zinc Finger Ran-binding Domain-containing Protein 3 (ZRANB3). J Biol Chem. 2016 Apr 8;291(15):8251-7. doi: 10.1074/jbc.M115.709733. Epub 2016, Feb 16. PMID:26884333 doi:http://dx.doi.org/10.1074/jbc.M115.709733
- ↑ Sebesta M, Cooper CDO, Ariza A, Carnie CJ, Ahel D. Structural insights into the function of ZRANB3 in replication stress response. Nat Commun. 2017 Jun 16;8:15847. doi: 10.1038/ncomms15847. PMID:28621305 doi:http://dx.doi.org/10.1038/ncomms15847
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