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Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms

Douse, Christopher H LU ; Bloor, Stuart ; Liu, Yangci ; Shamin, Maria ; Tchasovnikarova, Iva A ; Timms, Richard T ; Lehner, Paul J and Modis, Yorgo (2018) In Nature Communications 9.
Abstract

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... (More)

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.

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organization
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Contribution to journal
publication status
published
keywords
Adenosine Triphosphatases/metabolism, Adenosine Triphosphate/metabolism, Animals, Charcot-Marie-Tooth Disease/genetics, Crystallography, X-Ray, DNA/metabolism, Epigenesis, Genetic, Gene Silencing, HEK293 Cells, HeLa Cells, Humans, Muscular Atrophy, Spinal, Mutation, Missense, Nervous System Diseases/genetics, Protein Binding, Protein Conformation, Protein Multimerization, Sf9 Cells, Transcription Factors/chemistry, Zinc Fingers
in
Nature Communications
volume
9
article number
651
publisher
Nature Publishing Group
external identifiers
  • pmid:29440755
  • scopus:85042027371
ISSN
2041-1723
DOI
10.1038/s41467-018-03045-x
language
English
LU publication?
yes
id
f798777e-6300-4be3-95d5-7bc0776d4b48
date added to LUP
2022-09-16 10:37:30
date last changed
2024-04-03 19:55:17
@article{f798777e-6300-4be3-95d5-7bc0776d4b48,
  abstract     = {{<p>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.</p>}},
  author       = {{Douse, Christopher H and Bloor, Stuart and Liu, Yangci and Shamin, Maria and Tchasovnikarova, Iva A and Timms, Richard T and Lehner, Paul J and Modis, Yorgo}},
  issn         = {{2041-1723}},
  keywords     = {{Adenosine Triphosphatases/metabolism; Adenosine Triphosphate/metabolism; Animals; Charcot-Marie-Tooth Disease/genetics; Crystallography, X-Ray; DNA/metabolism; Epigenesis, Genetic; Gene Silencing; HEK293 Cells; HeLa Cells; Humans; Muscular Atrophy, Spinal; Mutation, Missense; Nervous System Diseases/genetics; Protein Binding; Protein Conformation; Protein Multimerization; Sf9 Cells; Transcription Factors/chemistry; Zinc Fingers}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Neuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms}},
  url          = {{http://dx.doi.org/10.1038/s41467-018-03045-x}},
  doi          = {{10.1038/s41467-018-03045-x}},
  volume       = {{9}},
  year         = {{2018}},
}