5ofa - Revision history

OCA at 07:27, 1 May 2024

2024-05-01T07:27:45Z

←Older revision		Revision as of 07:27, 1 May 2024
Line 12:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/MORC2_HUMAN 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).<ref>PMID:20110259</ref> <ref>PMID:20225202</ref> <ref>PMID:24286864</ref>		[https://www.uniprot.org/uniprot/MORC2_HUMAN 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).<ref>PMID:20110259</ref> <ref>PMID:20225202</ref> <ref>PMID:24286864</ref>
-	<div style="background-color:#fffaf0;">
-	== 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>
-	</div>
-	<div class="pdbe-citations 5ofa" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 16:47, 13 December 2023

2023-12-13T16:47:58Z

←Older revision		Revision as of 16:47, 13 December 2023
Line 1:		Line 1:

	==Crystal structure of human MORC2 (residues 1-603) with spinal muscular atrophy mutation T424R==		==Crystal structure of human MORC2 (residues 1-603) with spinal muscular atrophy mutation T424R==
-	<StructureSection load='5ofa' size='340' side='right' caption='[[5ofa]], [[Resolution\|resolution]] 2.57Å' scene=''>	+	<StructureSection load='5ofa' size='340' side='right'caption='[[5ofa]], [[Resolution\|resolution]] 2.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ofa]] 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=5OFA OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5OFA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ofa]] 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=5OFA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OFA FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.57Å</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='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5ofa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofa OCA], [~~http~~://pdbe.org/5ofa PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5ofa RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5ofa PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofa 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=5ofa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofa OCA], [https://pdbe.org/5ofa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ofa RCSB], [https://www.ebi.ac.uk/pdbsum/5ofa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofa ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/MORC2_HUMAN MORC2_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry.	+	[https://www.uniprot.org/uniprot/MORC2_HUMAN MORC2_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/MORC2_HUMAN 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).<ref>PMID:20110259</ref> <ref>PMID:20225202</ref> <ref>PMID:24286864</ref>	+	[https://www.uniprot.org/uniprot/MORC2_HUMAN 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).<ref>PMID:20110259</ref> <ref>PMID:20225202</ref> <ref>PMID:24286864</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Douse, C H~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Liu, Y~~]]	+	[[Category: Douse CH]]
-	[[Category: ~~Modis,~~ Y]]	+	[[Category: Liu Y]]
-	[[Category: ~~Charcot-marie-tooth disease]]~~	+	[[Category: Modis Y]]
-	~~[[Category: Chromatin remodeler]]~~	+
-	~~[[Category: Coiled-coil]]~~	+
-	~~[[Category: Cw domain]]~~	+
-	~~[[Category: Dna binding protein]]~~	+
-	~~[[Category: Epigenetic silencing]]~~	+
-	~~[[Category: Ghkl atpase]]~~	+
-	~~[[Category: Nuclear protein]]~~	+
-	~~[[Category: Spinal muscular atrophy]]~~	+
-	~~[[Category: Transcriptional repressor~~]]	+

OCA at 07:09, 28 February 2018

2018-02-28T07:09:17Z

←Older revision		Revision as of 07:09, 28 February 2018
Line 3:		Line 3:
	<StructureSection load='5ofa' size='340' side='right' caption='[[5ofa]], [[Resolution\|resolution]] 2.57Å' scene=''>		<StructureSection load='5ofa' size='340' side='right' caption='[[5ofa]], [[Resolution\|resolution]] 2.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ofa]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OFA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ofa]] 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=5OFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OFA FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</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=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</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=5ofa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofa OCA], [http://pdbe.org/5ofa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ofa RCSB], [http://www.ebi.ac.uk/pdbsum/5ofa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofa 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=5ofa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofa OCA], [http://pdbe.org/5ofa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ofa RCSB], [http://www.ebi.ac.uk/pdbsum/5ofa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofa ProSAT]</span></td></tr>
	</table>		</table>
Line 13:		Line 14:
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	~~Dominant~~ mutations in ~~the~~ MORC2 ~~gene have recently been shown to~~ cause ~~axonal~~ Charcot-Marie-Tooth ~~(CMT)~~ disease~~, but the cellular function of MORC2 is poorly understood~~. ~~Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we~~ identified MORC2 as an ~~essential gene required for~~ epigenetic silencing by the HUSH ~~complex~~. ~~HUSH recruits~~ MORC2 ~~to target sites in heterochromatin~~. ~~We exploited~~ a ~~new method~~, ~~differential viral accessibility (DIVA), to show~~ that ~~loss~~ of MORC2 ~~results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The~~ ATPase ~~activity of MORC2 is critical for~~ HUSH-~~mediated~~ silencing~~, and~~ the ~~most common alteration affecting~~ the ATPase ~~domain in CMT patients (p.Arg252Trp) hyperactivates HUSH~~-~~mediated repression in neuronal cells~~. These ~~data define a critical role for MORC2 in epigenetic silencing by~~ the HUSH ~~complex and provide~~ a ~~mechanistic~~ basis ~~underpinning the role of~~ MORC2 ~~mutations in CMT disease~~.	+	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.

-	~~Hyperactivation of HUSH complex function~~ by ~~Charcot-Marie-Tooth disease mutation in MORC2~~.,Tchasovnikarova IA, Timms RT, ~~Douse CH, Roberts RC, Dougan G, Kingston RE~~, Modis Y~~, Lehner PJ~~ Nat ~~Genet~~. ~~2017 Jul~~;49(7):~~1035-1044~~. doi: 10.1038/~~ng.3878. Epub 2017 Jun 5~~. PMID:~~28581500~~<ref>PMID:~~28581500~~</ref>	+	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>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Douse, C H]]		[[Category: Douse, C H]]
	[[Category: Liu, Y]]		[[Category: Liu, Y]]

OCA at 06:26, 15 February 2018

2018-02-15T06:26:08Z

←Older revision		Revision as of 06:26, 15 February 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5ofa is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of human MORC2 (residues 1-603) with spinal muscular atrophy mutation T424R==
		+	<StructureSection load='5ofa' size='340' side='right' caption='[[5ofa]], [[Resolution\|resolution]] 2.57Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5ofa]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OFA FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5ofa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofa OCA], [http://pdbe.org/5ofa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ofa RCSB], [http://www.ebi.ac.uk/pdbsum/5ofa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofa ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/MORC2_HUMAN MORC2_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MORC2_HUMAN 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).<ref>PMID:20110259</ref> <ref>PMID:20225202</ref> <ref>PMID:24286864</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR-Cas9-mediated forward genetic screen, we identified MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploited a new method, differential viral accessibility (DIVA), to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common alteration affecting the ATPase domain in CMT patients (p.Arg252Trp) hyperactivates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease.

-	~~Authors~~:	+	Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.,Tchasovnikarova IA, Timms RT, Douse CH, Roberts RC, Dougan G, Kingston RE, Modis Y, Lehner PJ Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5. PMID:28581500<ref>PMID:28581500</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5ofa" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Douse, C H]]
		+	[[Category: Liu, Y]]
		+	[[Category: Modis, Y]]
		+	[[Category: Charcot-marie-tooth disease]]
		+	[[Category: Chromatin remodeler]]
		+	[[Category: Coiled-coil]]
		+	[[Category: Cw domain]]
		+	[[Category: Dna binding protein]]
		+	[[Category: Epigenetic silencing]]
		+	[[Category: Ghkl atpase]]
		+	[[Category: Nuclear protein]]
		+	[[Category: Spinal muscular atrophy]]
		+	[[Category: Transcriptional repressor]]

OCA at 04:46, 20 December 2017

2017-12-20T04:46:26Z

←Older revision		Revision as of 04:46, 20 December 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5ofa is ON HOLD	+	The entry 5ofa is ON HOLD until Paper Publication

	Authors:		Authors:

OCA at 05:42, 13 December 2017

2017-12-13T05:42:40Z

←Older revision		Revision as of 05:42, 13 December 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5ofa is ON HOLD ~~until Paper Publication~~	+	The entry 5ofa is ON HOLD

	Authors:		Authors:

OCA: Protected "5ofa" [edit=sysop:move=sysop]

2017-09-27T12:22:34Z

Protected "5ofa" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:22, 27 September 2017

OCA: New page: '''Unreleased structure''' The entry 5ofa is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

2017-09-27T12:22:33Z

New page: '''Unreleased structure''' The entry 5ofa is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5ofa is ON HOLD until Paper Publication

Authors:

Description:
[[Category: Unreleased Structures]]