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TitleMORC2 is a phosphorylation-dependent DNA compaction machine.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 5606, Year 2025
Publish dateJul 1, 2025
AuthorsWinnie Tan / Jeongveen Park / Hariprasad Venugopal / Jieqiong Lou / Prabavi Shayana Dias / Pedro L Baldoni / Kyoung-Wook Moon / Toby A Dite / Christine R Keenan / Alexandra D Gurzau / Joonyoung Lee / Timothy M Johanson / Andrew Leis / Jumana Yousef / Vineet Vaibhav / Laura F Dagley / Ching-Seng Ang / Laura D Corso / Chen Davidovich / Stephin J Vervoort / Gordon K Smyth / Marnie E Blewitt / Rhys S Allan / Elizabeth Hinde / Sheena D'Arcy / Je-Kyung Ryu / Shabih Shakeel /
PubMed AbstractThe Microrchidia (MORC) family of chromatin-remodelling ATPases is pivotal in forming higher-order chromatin structures that suppress transcription. The exact mechanisms of MORC-induced chromatin ...The Microrchidia (MORC) family of chromatin-remodelling ATPases is pivotal in forming higher-order chromatin structures that suppress transcription. The exact mechanisms of MORC-induced chromatin remodelling have been elusive. Here, we report an in vitro reconstitution of full-length MORC2, the most commonly mutated MORC member, linked to various cancers and neurological disorders. MORC2 possesses multiple DNA-binding sites that undergo structural rearrangement upon DNA binding. MORC2 locks onto the DNA using its C-terminal domain (CTD) and acts as a clamp. A conserved phosphate-interacting motif within the CTD was found to regulate ATP hydrolysis and cooperative DNA binding. Importantly, MORC2 mediates chromatin remodelling via ATP hydrolysis-dependent DNA compaction in vitro, regulated by the phosphorylation state of its CTD. These findings position MORC2 CTD phosphorylation as a critical regulator of chromatin remodelling and a promising therapeutic target.
External linksNat Commun / PubMed:40593625 / PubMed Central
MethodsEM (single particle)
Resolution1.95 - 3.24 Å
Structure data

EMDB-45474, PDB-9cdf:
Structure of MORC2 PD mutant binding to AMP-PNP
Method: EM (single particle) / Resolution: 2.39 Å

EMDB-45475, PDB-9cdg:
MORC2 ATPase dead mutant - S87A
Method: EM (single particle) / Resolution: 2.43 Å

EMDB-45476, PDB-9cdh:
MORC2 PD mutant with DNA
Method: EM (single particle) / Resolution: 1.95 Å

EMDB-45477, PDB-9cdi:
MORC2 ATPase structure
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-45478, PDB-9cdj:
MORC2 ATPase with DNA
Method: EM (single particle) / Resolution: 2.49 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
KeywordsDNA BINDING PROTEIN / Chromatin remodeller / complex / ATPase / ATPase dead / DNA compaction / AMP-PNP / DNA

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