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dc.contributor.authorDouse, Christopher
dc.contributor.authorBloor, Stuart
dc.contributor.authorLiu, Yangci
dc.contributor.authorShamin, Maria
dc.contributor.authorTchasovnikarova, Iva
dc.contributor.authorTimms, Richard
dc.contributor.authorLehner, Paul
dc.contributor.authorModis, Yorgo
dc.date.accessioned2019-02-26T18:36:45Z
dc.date.available2019-02-26T18:36:45Z
dc.date.issued2018-02-13
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290007
dc.description.abstractMissense 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 HUSH complex. 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 modulation of HUSH function, thus providing a molecular basis for understanding MORC2-associated neuropathies.
dc.description.sponsorshipWellcome Trust (101908/Z/13/Z and 101835/Z/13/Z) BBSRC (BB/N011791/1)
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleNeuropathic mutations in MORC2 perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms
dc.typeArticle
prism.number651
prism.publicationDate2018
prism.publicationNameNature Communications
prism.volume9
dc.identifier.doi10.17863/CAM.37234
dcterms.dateAccepted2018-01-16
rioxxterms.versionofrecord10.1038/s41467-018-03045-x
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2018-02-13
dc.contributor.orcidDouse, Christopher [0000-0002-1604-8944]
dc.contributor.orcidTimms, Richard [0000-0001-7275-597X]
dc.contributor.orcidLehner, Paul [0000-0001-9383-1054]
dc.contributor.orcidModis, Yorgo [0000-0002-6084-0429]
dc.publisher.urlhttps://www.nature.com/articles/s41467-018-03045-x
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (101908/Z/13/Z)
cam.issuedOnline2018-02-13
dc.identifier.urlhttps://www.nature.com/articles/s41467-018-03045-x


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International