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==Crystal structure of the CPS-6 mutant Q130K==
==Crystal structure of the CPS-6 mutant Q130K==
<StructureSection load='4qn0' size='340' side='right' caption='[[4qn0]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
<StructureSection load='4qn0' size='340' side='right' caption='[[4qn0]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
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</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3s5b|3s5b]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3s5b|3s5b]]</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=4qn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qn0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qn0 RCSB], [http://www.ebi.ac.uk/pdbsum/4qn0 PDBsum]</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=4qn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qn0 OCA], [http://pdbe.org/4qn0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qn0 RCSB], [http://www.ebi.ac.uk/pdbsum/4qn0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qn0 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Endonuclease G (EndoG) is a mitochondrial protein that traverses to the nucleus and participates in chromosomal DNA degradation during apoptosis in yeast, worms, flies, and mammals. However, it remains unclear how EndoG binds and digests DNA. Here we show that the Caenorhabditis elegans CPS-6, a homolog of EndoG, is a homodimeric Mg(2+)-dependent nuclease, binding preferentially to G-tract DNA in the optimum low salt buffer at pH 7. The crystal structure of CPS-6 was determined at 1.8 A resolution, revealing a mixed alphabeta topology with the two betabetaalpha-metal finger nuclease motifs located distantly at the two sides of the dimeric enzyme. A structural model of the CPS-6-DNA complex suggested a positively charged DNA-binding groove near the Mg(2+)-bound active site. Mutations of four aromatic and basic residues: Phe(122), Arg(146), Arg(156), and Phe(166), in the protein-DNA interface significantly reduced the DNA binding and cleavage activity of CPS-6, confirming that these residues are critical for CPS-6-DNA interactions. In vivo transformation rescue experiments further showed that the reduced DNase activity of CPS-6 mutants was positively correlated with its diminished cell killing activity in C. elegans. Taken together, these biochemical, structural, mutagenesis, and in vivo data reveal a molecular basis of how CPS-6 binds and hydrolyzes DNA to promote cell death.
Endonuclease G (EndoG) is a mitochondrial protein that is released from mitochondria and relocated into the nucleus to promote chromosomal DNA fragmentation during apoptosis. Here, we show that oxidative stress causes cell-death defects in C. elegans through an EndoG-mediated cell-death pathway. In response to high reactive oxygen species (ROS) levels, homodimeric CPS-6-the C. elegans homolog of EndoG-is dissociated into monomers with diminished nuclease activity. Conversely, the nuclease activity of CPS-6 is enhanced, and its dimeric structure is stabilized by its interaction with the worm AIF homolog, WAH-1, which shifts to disulfide cross-linked dimers under high ROS levels. CPS-6 thus acts as a ROS sensor to regulate the life and death of cells. Modulation of the EndoG dimer conformation could present an avenue for prevention and treatment of diseases resulting from oxidative stress.


Structural insights into apoptotic DNA degradation by CED-3 protease suppressor-6 (CPS-6) from Caenorhabditis elegans.,Lin JL, Nakagawa A, Lin CL, Hsiao YY, Yang WZ, Wang YT, Doudeva LG, Skeen-Gaar RR, Xue D, Yuan HS J Biol Chem. 2012 Mar 2;287(10):7110-20. Epub 2012 Jan 5. PMID:22223640<ref>PMID:22223640</ref>
Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G.,Lin JL, Nakagawa A, Skeen-Gaar R, Yang WZ, Zhao P, Zhang Z, Ge X, Mitani S, Xue D, Yuan HS Cell Rep. 2016 Jul 12;16(2):279-87. doi: 10.1016/j.celrep.2016.05.090. Epub 2016 , Jun 23. PMID:27346342<ref>PMID:27346342</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4qn0" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Revision as of 11:06, 27 July 2016

Crystal structure of the CPS-6 mutant Q130KCrystal structure of the CPS-6 mutant Q130K

Structural highlights

4qn0 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[NUCG_CAEEL] Endonuclease important for programmed cell death; it mediates apoptotic DNA fragmentation.

Publication Abstract from PubMed

Endonuclease G (EndoG) is a mitochondrial protein that is released from mitochondria and relocated into the nucleus to promote chromosomal DNA fragmentation during apoptosis. Here, we show that oxidative stress causes cell-death defects in C. elegans through an EndoG-mediated cell-death pathway. In response to high reactive oxygen species (ROS) levels, homodimeric CPS-6-the C. elegans homolog of EndoG-is dissociated into monomers with diminished nuclease activity. Conversely, the nuclease activity of CPS-6 is enhanced, and its dimeric structure is stabilized by its interaction with the worm AIF homolog, WAH-1, which shifts to disulfide cross-linked dimers under high ROS levels. CPS-6 thus acts as a ROS sensor to regulate the life and death of cells. Modulation of the EndoG dimer conformation could present an avenue for prevention and treatment of diseases resulting from oxidative stress.

Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G.,Lin JL, Nakagawa A, Skeen-Gaar R, Yang WZ, Zhao P, Zhang Z, Ge X, Mitani S, Xue D, Yuan HS Cell Rep. 2016 Jul 12;16(2):279-87. doi: 10.1016/j.celrep.2016.05.090. Epub 2016 , Jun 23. PMID:27346342[1]

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

References

  1. ↑ Lin JL, Nakagawa A, Skeen-Gaar R, Yang WZ, Zhao P, Zhang Z, Ge X, Mitani S, Xue D, Yuan HS. Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G. Cell Rep. 2016 Jul 12;16(2):279-87. doi: 10.1016/j.celrep.2016.05.090. Epub 2016 , Jun 23. PMID:27346342 doi:http://dx.doi.org/10.1016/j.celrep.2016.05.090

4qn0, resolution 2.74Å

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