6mdx

From Proteopedia

(Difference between revisions)

Current revision

Mechanism of protease dependent DPC repair

Structural highlights

6mdx is a 2 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 1.55Å
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

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6mdx"

@@ Line 3: / Line 3: @@
 <StructureSection load='6mdx' size='340' side='right'caption='[[6mdx]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mdx]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MDX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MDX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mdx]] 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=6MDX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MDX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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]] 1.55&#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>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=6mdx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mdx OCA], [http://pdbe.org/6mdx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mdx RCSB], [http://www.ebi.ac.uk/pdbsum/6mdx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mdx 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=6mdx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mdx OCA], [https://pdbe.org/6mdx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mdx RCSB], [https://www.ebi.ac.uk/pdbsum/6mdx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mdx ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[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: Dna binding protein-dna complex]]
-[[Category: Dpc repair]]
-[[Category: Protease]]

6mdx

From Proteopedia

Current revision

Mechanism of protease dependent DPC repair

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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