6mdw: Difference between revisions

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<StructureSection load='6mdw' size='340' side='right'caption='[[6mdw]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
<StructureSection load='6mdw' size='340' side='right'caption='[[6mdw]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6mdw]] is a 1 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=6MDW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MDW FirstGlance]. <br>
<table><tr><td colspan='2'>[[6mdw]] is a 1 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=6MDW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MDW FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</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]] 1.5&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLZ:N-METHYL-LYSINE'>MLZ</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=MLZ:N-METHYL-LYSINE'>MLZ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SPRTN, C1orf124, DVC1, UNQ1880/PRO4323 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6mdw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mdw OCA], [https://pdbe.org/6mdw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mdw RCSB], [https://www.ebi.ac.uk/pdbsum/6mdw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mdw ProSAT]</span></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=6mdw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mdw OCA], [http://pdbe.org/6mdw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mdw RCSB], [http://www.ebi.ac.uk/pdbsum/6mdw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mdw ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/SPRTN_HUMAN SPRTN_HUMAN]] Progeroid features-hepatocellular carcinoma predisposition syndrome. The disease is caused by mutations affecting the gene represented in this entry.  
[https://www.uniprot.org/uniprot/SPRTN_HUMAN SPRTN_HUMAN] Progeroid features-hepatocellular carcinoma predisposition syndrome. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/SPRTN_HUMAN SPRTN_HUMAN]] Regulator of UV-induced DNA damage response: acts as a 'reader' of ubiquitinated PCNA that enhances RAD18-mediated PCNA ubiquitination and translesion DNA synthesis (TLS). Recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis. Acts as a regulator of TLS by recruiting VCP/p97 to sites of DNA damage, possibly leading to extraction of DNA polymerase eta (POLH) by VCP/p97 to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.<ref>PMID:22681887</ref> <ref>PMID:22894931</ref> <ref>PMID:22902628</ref> <ref>PMID:22987070</ref> <ref>PMID:23042605</ref> <ref>PMID:23042607</ref>
[https://www.uniprot.org/uniprot/SPRTN_HUMAN SPRTN_HUMAN] Regulator of UV-induced DNA damage response: acts as a 'reader' of ubiquitinated PCNA that enhances RAD18-mediated PCNA ubiquitination and translesion DNA synthesis (TLS). Recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis. Acts as a regulator of TLS by recruiting VCP/p97 to sites of DNA damage, possibly leading to extraction of DNA polymerase eta (POLH) by VCP/p97 to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.<ref>PMID:22681887</ref> <ref>PMID:22894931</ref> <ref>PMID:22902628</ref> <ref>PMID:22987070</ref> <ref>PMID:23042605</ref> <ref>PMID:23042607</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: Chen, Z]]
[[Category: Chen Z]]
[[Category: Li, F]]
[[Category: Li F]]
[[Category: Raczynska, J]]
[[Category: Raczynska J]]
[[Category: Yu, H]]
[[Category: Yu H]]
[[Category: Dna binding protein]]
[[Category: Dpc repair protease]]

Latest revision as of 09:29, 11 October 2023

Mechanism of protease dependent DPC repairMechanism of protease dependent DPC repair

Structural highlights

6mdw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.5Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SPRTN_HUMAN Progeroid features-hepatocellular carcinoma predisposition syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

SPRTN_HUMAN Regulator of UV-induced DNA damage response: acts as a 'reader' of ubiquitinated PCNA that enhances RAD18-mediated PCNA ubiquitination and translesion DNA synthesis (TLS). Recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis. Acts as a regulator of TLS by recruiting VCP/p97 to sites of DNA damage, possibly leading to extraction of DNA polymerase eta (POLH) by VCP/p97 to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

The DNA-dependent metalloprotease Spartan (SPRTN) cleaves DNA-protein crosslinks (DPCs) and protects cells from DPC-induced genome instability. Germline mutations of SPRTN are linked to human Ruijs-Aalfs syndrome (RJALS) characterized by progeria and early-onset hepatocellular carcinoma. The mechanism of DNA-mediated activation of SPRTN is not understood. Here, we report the crystal structure of the human SPRTN SprT domain bound to single-stranded DNA (ssDNA). Our structure reveals a Zn(2+)-binding sub-domain (ZBD) in SprT that shields its active site located in the metalloprotease sub-domain (MPD). The narrow catalytic groove between MPD and ZBD only permits cleavage of flexible substrates. The ZBD contains an ssDNA-binding site, with a DNA-base-binding pocket formed by aromatic residues. Mutations of ssDNA-binding residues diminish the protease activity of SPRTN. We propose that the ZBD contributes to the ssDNA specificity of SPRTN, restricts the access of globular substrates, and positions DPCs, which may need to be partially unfolded, for optimal cleavage.

Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan.,Li F, Raczynska JE, Chen Z, Yu H Cell Rep. 2019 Mar 19;26(12):3336-3346.e4. doi: 10.1016/j.celrep.2019.02.082. PMID:30893605[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Centore RC, Yazinski SA, Tse A, Zou L. Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response. Mol Cell. 2012 Jun 8;46(5):625-35. doi: 10.1016/j.molcel.2012.05.020. PMID:22681887 doi:http://dx.doi.org/10.1016/j.molcel.2012.05.020
  2. ↑ Machida Y, Kim MS, Machida YJ. Spartan/C1orf124 is important to prevent UV-induced mutagenesis. Cell Cycle. 2012 Sep 15;11(18):3395-402. doi: 10.4161/cc.21694. Epub 2012 Aug 16. PMID:22894931 doi:http://dx.doi.org/10.4161/cc.21694
  3. ↑ Ghosal G, Leung JW, Nair BC, Fong KW, Chen J. Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. J Biol Chem. 2012 Oct 5;287(41):34225-33. doi: 10.1074/jbc.M112.400135. Epub 2012, Aug 17. PMID:22902628 doi:http://dx.doi.org/10.1074/jbc.M112.400135
  4. ↑ Juhasz S, Balogh D, Hajdu I, Burkovics P, Villamil MA, Zhuang Z, Haracska L. Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance. Nucleic Acids Res. 2012 Nov;40(21):10795-808. doi: 10.1093/nar/gks850. Epub 2012 , Sep 16. PMID:22987070 doi:http://dx.doi.org/10.1093/nar/gks850
  5. ↑ Mosbech A, Gibbs-Seymour I, Kagias K, Thorslund T, Beli P, Povlsen L, Nielsen SV, Smedegaard S, Sedgwick G, Lukas C, Hartmann-Petersen R, Lukas J, Choudhary C, Pocock R, Bekker-Jensen S, Mailand N. DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. Nat Struct Mol Biol. 2012 Nov;19(11):1084-92. doi: 10.1038/nsmb.2395. Epub 2012, Oct 7. PMID:23042605 doi:10.1038/nsmb.2395
  6. ↑ Davis EJ, Lachaud C, Appleton P, Macartney TJ, Nathke I, Rouse J. DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. Nat Struct Mol Biol. 2012 Nov;19(11):1093-100. doi: 10.1038/nsmb.2394. Epub 2012 , Oct 7. PMID:23042607 doi:10.1038/nsmb.2394
  7. ↑ Li F, Raczynska JE, Chen Z, Yu H. Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan. Cell Rep. 2019 Mar 19;26(12):3336-3346.e4. doi: 10.1016/j.celrep.2019.02.082. PMID:30893605 doi:http://dx.doi.org/10.1016/j.celrep.2019.02.082

6mdw, resolution 1.50Å

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