What question did this study set out to answer?

To elucidate the structural mechanisms by which disease-associated MORC2 mutations alter its ATPase dimerization dynamics and perturb epigenetic gene silencing.

February 7, 2018Nature CommunicationsOpen Access

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

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Authors

CDChristopher H. DouseLund University SBStuart BloorUniversity of Cambridge YLYangci LiuMRC Laboratory of Molecular Biology

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Implication

Structural and biochemical analysis uncovers how neuropathic MORC2 mutations alter ATPase dimerization and epigenetic silencing, highlighting a molecular basis for Charcot-Marie-Tooth disease.

Key Points

To elucidate the structural mechanisms by which disease-associated MORC2 mutations alter its ATPase dimerization dynamics and perturb epigenetic gene silencing.
Determined crystal structures of wild-type and neuropathic human MORC2 fragments containing the GHKL-type ATPase module and CW-type zinc finger.
Assayed the biochemical and cellular activities of MORC2 variants to assess ATP binding, dimerization dynamics, DNA binding, and human silencing hub (HUSH)-dependent silencing.
Demonstrated that ATP-dependent dimerization and DNA binding of the MORC2 ATPase module are essential for transducing HUSH-mediated epigenetic silencing.
Identified a hinged, functionally critical coiled-coil insertion in the MORC2 fragment that is absent in other GHKL-family ATPases.
Showed that neuropathic mutations perturb dimerization dynamics through distinct structural mechanisms, including destabilizing the ATPase-CW module, trapping the ATP lid, and disrupting the dimer interface.

Cite This Study

Douse et al. (2018) studied this question.

synapsesocial.com/papers/6a7cda3dccf86f44befebeda https://doi.org/10.1038/s41467-018-03045-x

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Implication

Structural and biochemical analysis uncovers how neuropathic MORC2 mutations alter ATPase dimerization and epigenetic silencing, highlighting a molecular basis for Charcot-Marie-Tooth disease.

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

Discussion

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Implication

Key Points

Cite This Study

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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