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Molecular mechanism of the MORC4 ATPase activation

Adam H Tencer1, Khan L Cox2, Gregory M Wright1

  • 1Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Nature Communications
|October 30, 2020
PubMed

Insights

Human Microrchidia 4 (MORC4) has ATPase activity dependent on DNA binding. MORC4 binds nucleosomes, impacting DNA accessibility and cell cycle progression, with a unique activation mechanism.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • Human Microrchidia 4 (MORC4) is implicated in pancreatitis, inflammation, and cancer.
  • The molecular functions and activation mechanisms of MORC4 are largely unknown.

Purpose of the Study:

  • To elucidate the structure-function relationship of MORC4.
  • To define the molecular mechanism governing MORC4 activation.

Main Methods:

  • Enzymatic and binding assays were employed to characterize MORC4 activity.
  • Crystal structure determination of the MORC4 ATPaseCW cassette.
  • Site-directed mutagenesis studies were performed.
  • Cellular assays assessed MORC4's role in nuclear body formation and cell cycle progression.

Main Results:

  • MORC4 exhibits DNA-dependent ATPase activity, requiring both ATPase and CW domains.
  • Crystal structure reveals distinct DNA-binding and histone/ATPase-binding sites on the CW domain.
  • MORC4 binds to nucleosome core particles (NCPs), promoting DNA wrapping and hindering transcription factor binding.
  • MORC4 mediates nuclear body formation and S-phase progression, dependent on its CW domain and catalytic activity.

Conclusions:

  • MORC4 activation mechanism is distinct from other MORC family members.
  • MORC4 plays a significant role in regulating DNA accessibility within nucleosomes.
  • MORC4 is crucial for nuclear organization and cell cycle control.

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