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

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Christopher H Douse1, Stuart Bloor2, Yangci Liu3

  • 1Department of Medicine, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0QH, UK. cdouse@mrc-lmb.cam.ac.uk.

Nature Communications
|February 15, 2018
PubMed

Insights

Missense mutations in MORC2 cause neuropathies. This study reveals how MORC2 variants disrupt HUSH-mediated epigenetic silencing by altering its dimerization and DNA binding, explaining disease mechanisms.

Area of Science:

  • Molecular Biology
  • Genetics
  • Structural Biology

Background:

  • Missense mutations in MORC2 are linked to neuropathies like spinal muscular atrophy and Charcot-Marie-Tooth disease.
  • MORC2 functions as an effector in the human silencing hub (HUSH) complex, mediating epigenetic gene silencing.

Purpose of the Study:

  • To investigate the biochemical and cellular activities of MORC2 variants.
  • To elucidate the structural basis of MORC2 function and disease-associated mutations using crystal structures.

Main Methods:

  • Biochemical assays to study MORC2 variant activities.
  • Crystal structure determination of wild-type and mutant MORC2 fragments (ATPase module and zinc finger).
  • Cellular assays to assess HUSH-dependent silencing modulation.

Main Results:

  • The MORC2 ATPase module dimerizes upon ATP binding, facilitated by a unique coiled-coil insertion.
  • Dimerization and DNA binding of the MORC2 ATPase module are crucial for HUSH-dependent silencing.
  • Disease-associated mutations impair MORC2 dimerization through various structural mechanisms, affecting HUSH function.

Conclusions:

  • Structural and biochemical insights into MORC2 function and its role in HUSH-mediated epigenetic silencing.
  • Provides a molecular understanding of how MORC2 mutations lead to neuropathies by disrupting silencing pathways.

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