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| | ==Crystal structure of the human FEN1-PCNA complex== | | ==Crystal structure of the human FEN1-PCNA complex== |
| - | <StructureSection load='1ul1' size='340' side='right' caption='[[1ul1]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='1ul1' size='340' side='right'caption='[[1ul1]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1ul1]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. The June 2012 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Sliding Clamps'' by David Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2012_6 10.2210/rcsb_pdb/mom_2012_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UL1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1UL1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1ul1]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The June 2012 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Sliding Clamps'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2012_6 10.2210/rcsb_pdb/mom_2012_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UL1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1UL1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1b43|1b43]], [[1a76|1a76]], [[1axc|1axc]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=1ul1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ul1 OCA], [http://pdbe.org/1ul1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ul1 RCSB], [http://www.ebi.ac.uk/pdbsum/1ul1 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=1ul1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ul1 OCA], [https://pdbe.org/1ul1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ul1 RCSB], [https://www.ebi.ac.uk/pdbsum/1ul1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ul1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FEN1_HUMAN FEN1_HUMAN]] Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.<ref>PMID:7961795</ref> <ref>PMID:8621570</ref> <ref>PMID:10744741</ref> <ref>PMID:11986308</ref> <ref>PMID:18443037</ref> <ref>PMID:20729856</ref> [[http://www.uniprot.org/uniprot/PCNA_HUMAN PCNA_HUMAN]] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.<ref>PMID:19443450</ref> <ref>PMID:18719106</ref> | + | [https://www.uniprot.org/uniprot/FEN1_HUMAN FEN1_HUMAN] Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.<ref>PMID:7961795</ref> <ref>PMID:8621570</ref> <ref>PMID:10744741</ref> <ref>PMID:11986308</ref> <ref>PMID:18443037</ref> <ref>PMID:20729856</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/ul/1ul1_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ul/1ul1_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=1ul1 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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| | ==See Also== | | ==See Also== |
| - | *[[Endonuclease|Endonuclease]] | + | *[[Endonuclease 3D structures|Endonuclease 3D structures]] |
| - | *[[Proliferating Cell Nuclear Antigen|Proliferating Cell Nuclear Antigen]] | + | *[[Proliferating cell nuclear antigen 3D structures|Proliferating cell nuclear antigen 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: RCSB PDB Molecule of the Month]] | | [[Category: RCSB PDB Molecule of the Month]] |
| | [[Category: Sliding Clamps]] | | [[Category: Sliding Clamps]] |
| - | [[Category: Fukuda, K]] | + | [[Category: Fukuda K]] |
| - | [[Category: Hakoshima, T]] | + | [[Category: Hakoshima T]] |
| - | [[Category: Hamada, K]] | + | [[Category: Hamada K]] |
| - | [[Category: Kitano, K]] | + | [[Category: Kitano K]] |
| - | [[Category: Morioka, H]] | + | [[Category: Morioka H]] |
| - | [[Category: Ohtsuka, E]] | + | [[Category: Ohtsuka E]] |
| - | [[Category: Okada, K]] | + | [[Category: Okada K]] |
| - | [[Category: Sakurai, S]] | + | [[Category: Sakurai S]] |
| - | [[Category: Uchida, M]] | + | [[Category: Uchida M]] |
| - | [[Category: Yamaguchi, H]] | + | [[Category: Yamaguchi H]] |
| - | [[Category: Dna clamp]]
| + | |
| - | [[Category: Dna repair]]
| + | |
| - | [[Category: Dna-binding protein]]
| + | |
| - | [[Category: Flap dna]]
| + | |
| - | [[Category: Flap endonuclease]]
| + | |
| - | [[Category: Hydrolase-dna binding protein complex]]
| + | |
| - | [[Category: Protein complex]]
| + | |
| - | [[Category: Replication]]
| + | |
| - | [[Category: Sliding clamp]]
| + | |
| Structural highlights
Function
FEN1_HUMAN Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.[1] [2] [3] [4] [5] [6]
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
Flap endonuclease-1 (FEN1) is a key enzyme for maintaining genomic stability and replication. Proliferating cell nuclear antigen (PCNA) binds FEN1 and stimulates its endonuclease activity. The structural basis of the FEN1-PCNA interaction was revealed by the crystal structure of the complex between human FEN1 and PCNA. The main interface involves the C-terminal tail of FEN1, which forms two beta-strands connected by a short helix, the betaA-alphaA-betaB motif, participating in beta-beta and hydrophobic interactions with PCNA. These interactions are similar to those previously observed for the p21CIP1/WAF1 peptide. However, this structure involving the full-length enzyme has revealed additional interfaces that are involved in the core domain. The interactions at the interfaces maintain the enzyme in an inactive 'locked-down' orientation and might be utilized in rapid DNA-tracking by preserving the central hole of PCNA for sliding along the DNA. A hinge region present between the core domain and the C-terminal tail of FEN1 would play a role in switching the FEN1 orientation from an inactive to an active orientation.
Structural basis for recruitment of human flap endonuclease 1 to PCNA.,Sakurai S, Kitano K, Yamaguchi H, Hamada K, Okada K, Fukuda K, Uchida M, Ohtsuka E, Morioka H, Hakoshima T EMBO J. 2005 Feb 23;24(4):683-93. Epub 2004 Dec 16. PMID:15616578[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Robins P, Pappin DJ, Wood RD, Lindahl T. Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I. J Biol Chem. 1994 Nov 18;269(46):28535-8. PMID:7961795
- ↑ Shen B, Nolan JP, Sklar LA, Park MS. Essential amino acids for substrate binding and catalysis of human flap endonuclease 1. J Biol Chem. 1996 Apr 19;271(16):9173-6. PMID:8621570
- ↑ Tom S, Henricksen LA, Bambara RA. Mechanism whereby proliferating cell nuclear antigen stimulates flap endonuclease 1. J Biol Chem. 2000 Apr 7;275(14):10498-505. PMID:10744741
- ↑ Qiu J, Bimston DN, Partikian A, Shen B. Arginine residues 47 and 70 of human flap endonuclease-1 are involved in DNA substrate interactions and cleavage site determination. J Biol Chem. 2002 Jul 5;277(27):24659-66. Epub 2002 May 1. PMID:11986308 doi:http://dx.doi.org/10.1074/jbc.M111941200
- ↑ Guo Z, Qian L, Liu R, Dai H, Zhou M, Zheng L, Shen B. Nucleolar localization and dynamic roles of flap endonuclease 1 in ribosomal DNA replication and damage repair. Mol Cell Biol. 2008 Jul;28(13):4310-9. doi: 10.1128/MCB.00200-08. Epub 2008 Apr, 28. PMID:18443037 doi:http://dx.doi.org/10.1128/MCB.00200-08
- ↑ Guo Z, Zheng L, Xu H, Dai H, Zhou M, Pascua MR, Chen QM, Shen B. Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat Chem Biol. 2010 Oct;6(10):766-73. doi: 10.1038/nchembio.422. Epub 2010 Aug, 22. PMID:20729856 doi:http://dx.doi.org/10.1038/nchembio.422
- ↑ Sakurai S, Kitano K, Yamaguchi H, Hamada K, Okada K, Fukuda K, Uchida M, Ohtsuka E, Morioka H, Hakoshima T. Structural basis for recruitment of human flap endonuclease 1 to PCNA. EMBO J. 2005 Feb 23;24(4):683-93. Epub 2004 Dec 16. PMID:15616578
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