|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6hvo' size='340' side='right'caption='[[6hvo]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='6hvo' size='340' side='right'caption='[[6hvo]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6hvo]] is a 6 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=6HVO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HVO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6hvo]] is a 6 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=6HVO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HVO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.1Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PCNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), POLD4, POLDS ([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=SO4:SULFATE+ION'>SO4</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=6hvo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hvo OCA], [http://pdbe.org/6hvo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hvo RCSB], [http://www.ebi.ac.uk/pdbsum/6hvo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hvo 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=6hvo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hvo OCA], [https://pdbe.org/6hvo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hvo RCSB], [https://www.ebi.ac.uk/pdbsum/6hvo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hvo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> [[http://www.uniprot.org/uniprot/DPOD4_HUMAN DPOD4_HUMAN]] As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity (PubMed:16510448, PubMed:19074196, PubMed:20334433). Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system (PubMed:24035200). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb (PubMed:24310611). Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196). Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival (PubMed:24022480).<ref>PMID:16510448</ref> <ref>PMID:19074196</ref> <ref>PMID:20334433</ref> <ref>PMID:24022480</ref> <ref>PMID:24035200</ref> <ref>PMID:24310611</ref> | + | [https://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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 19: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6hvo" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6hvo" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[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: Large Structures]] |
| - | [[Category: Biasio, A De]] | + | [[Category: Blanco FJ]] |
| - | [[Category: Blanco, F J]] | + | [[Category: De Biasio A]] |
| - | [[Category: Gonzalez-Magana, A]] | + | [[Category: Gonzalez-Magana A]] |
| - | [[Category: Rojas, A L]] | + | [[Category: Rojas AL]] |
| - | [[Category: Romano-Moreno, M]] | + | [[Category: Romano-Moreno M]] |
| - | [[Category: Crystal]]
| + | |
| - | [[Category: P12]]
| + | |
| - | [[Category: Pcna]]
| + | |
| - | [[Category: Pold4]]
| + | |
| - | [[Category: Polymerase delta]]
| + | |
| - | [[Category: Replication]]
| + | |
| Structural highlights
Function
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.[1] [2]
Publication Abstract from PubMed
Human DNA polymerase delta is essential for DNA replication and acts in conjunction with the processivity factor proliferating cell nuclear antigen (PCNA). Besides its catalytic subunit (p125), pol delta comprises three regulatory subunits (p50, p68, and p12). PCNA interacts with all of these subunits, but only the interaction with p68 has been structurally characterized. Here, we report solution NMR-, isothermal titration calorimetry-, and X-ray crystallography-based analyses of the p12-PCNA interaction, which takes part in the modulation of the rate and fidelity of DNA synthesis by pol delta. We show that p12 binds with micromolar affinity to the classical PIP-binding pocket of PCNA via a highly atypical PIP-box located at the p12 N terminus. Unlike the canonical PIP-box of p68, the PIP-box of p12 lacks the conserved glutamine, binds through a 2-fork plug made of an isoleucine and a tyrosine residue at +3 and +8 positions, respectively, and is stabilized by an aspartate at +6 position, which creates a network of intra-molecular hydrogen bonds. These findings add to growing evidence that PCNA can bind a diverse range of protein sequences that may be broadly grouped as PIP-like motifs as has been previously suggested.
The p12 subunit of human polymerase delta uses an atypical PIP-box for molecular recognition of proliferating cell nuclear antigen (PCNA).,Gonzalez-Magana A, Ibanez de Opakua A, Romano-Moreno M, Murciano-Calles J, Merino N, Luque I, Rojas AL, Onesti S, Blanco FJ, De Biasio A J Biol Chem. 2019 Jan 17. pii: RA118.006391. doi: 10.1074/jbc.RA118.006391. PMID:30655288[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Burkovics P, Hajdu I, Szukacsov V, Unk I, Haracska L. Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage. Nucleic Acids Res. 2009 Jul;37(13):4247-55. doi: 10.1093/nar/gkp357. Epub 2009, May 13. PMID:19443450 doi:10.1093/nar/gkp357
- ↑ Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K. Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12411-6. Epub 2008 Aug 21. PMID:18719106 doi:0805685105
- ↑ Gonzalez-Magana A, Ibanez de Opakua A, Romano-Moreno M, Murciano-Calles J, Merino N, Luque I, Rojas AL, Onesti S, Blanco FJ, De Biasio A. The p12 subunit of human polymerase delta uses an atypical PIP-box for molecular recognition of proliferating cell nuclear antigen (PCNA). J Biol Chem. 2019 Jan 17. pii: RA118.006391. doi: 10.1074/jbc.RA118.006391. PMID:30655288 doi:http://dx.doi.org/10.1074/jbc.RA118.006391
|
