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

Christopher H Douse,Maria Shamin,Paul J Lehner,Stuart Bloor,Iva A Tchasovnikarova,Yangci Liu,Richard T Timms,Yorgo Modis

doi:10.1038/s41467-018-03045-x

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 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.

Highlights

Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot–Marie–Tooth disease
Genetic studies have established that Microrchidia CW-type zinc finger (CW)-type zinc finger proteins (MORCs) family proteins have fundamentally important functions in epigenetic silencing across eukaryotic species1,4,5,8
We recently identified MORC2 as an effector of the human silencing hub (HUSH) complex and showed that MORC2 contributes to chromatin compaction across HUSH target loci

Summary

Introduction

Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot–Marie–Tooth disease. 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. 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, providing a molecular basis for understanding MORC2-associated neuropathies. Our data provide a molecular understanding of the multiple structural mechanisms underlying the neuropathic effects of MORC2 mutations

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Results

Conclusion