5ofb: Difference between revisions
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<StructureSection load='5ofb' size='340' side='right' caption='[[5ofb]], [[Resolution|resolution]] 2.02Å' scene=''> | <StructureSection load='5ofb' size='340' side='right' caption='[[5ofb]], [[Resolution|resolution]] 2.02Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5ofb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OFB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OFB FirstGlance]. <br> | <table><tr><td colspan='2'>[[5ofb]] is a 2 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=5OFB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OFB FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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">MORC2, KIAA0852, ZCWCC1 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ofb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofb OCA], [http://pdbe.org/5ofb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ofb RCSB], [http://www.ebi.ac.uk/pdbsum/5ofb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofb 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=5ofb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofb OCA], [http://pdbe.org/5ofb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ofb RCSB], [http://www.ebi.ac.uk/pdbsum/5ofb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofb ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the human silencing hub (HUSH). Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled-coil insertion absent in other GHKL ATPases. We find that dimerization and DNA binding of the MORC2 ATPase module transduce HUSH-dependent silencing. Disease mutations change the dynamics of dimerization by distinct structural mechanisms: destabilizing the ATPase-CW module, trapping the ATP lid, or perturbing the dimer interface. These defects lead to the modulation of HUSH function, thus providing a molecular basis for understanding MORC2-associated neuropathies. | |||
Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms.,Douse CH, Bloor S, Liu Y, Shamin M, Tchasovnikarova IA, Timms RT, Lehner PJ, Modis Y Nat Commun. 2018 Feb 13;9(1):651. doi: 10.1038/s41467-018-03045-x. PMID:29440755<ref>PMID:29440755</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Douse, C H]] | [[Category: Douse, C H]] | ||
[[Category: Liu, Y]] | [[Category: Liu, Y]] | ||
Revision as of 10:09, 28 February 2018
Crystal structure of human MORC2 (residues 1-603) with spinal muscular atrophy mutation S87LCrystal structure of human MORC2 (residues 1-603) with spinal muscular atrophy mutation S87L
Structural highlights
Disease[MORC2_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Function[MORC2_HUMAN] Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation (PubMed:24286864). May act as a transcriptional repressor (PubMed:20225202). Down-regulates CA9 expression (PubMed:20110259).[1] [2] [3] Publication Abstract from PubMedMissense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the human silencing hub (HUSH). Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. This fragment dimerizes upon binding ATP and contains a hinged, functionally critical coiled-coil insertion absent in other GHKL ATPases. We find that dimerization and DNA binding of the MORC2 ATPase module transduce HUSH-dependent silencing. Disease mutations change the dynamics of dimerization by distinct structural mechanisms: destabilizing the ATPase-CW module, trapping the ATP lid, or perturbing the dimer interface. These defects lead to the modulation of HUSH function, thus providing a molecular basis for understanding MORC2-associated neuropathies. Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms.,Douse CH, Bloor S, Liu Y, Shamin M, Tchasovnikarova IA, Timms RT, Lehner PJ, Modis Y Nat Commun. 2018 Feb 13;9(1):651. doi: 10.1038/s41467-018-03045-x. PMID:29440755[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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