Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic regulator that plays critical roles in gene regulation during development. Mutations in SMCHD1 were recently implicated in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), although the mechanistic basis remains of outstanding interest. We have previously shown that Smchd1 associates with chromatin via its homodimeric C-terminal hinge domain, yet little is known about the function of the putative GHKL (gyrase, Hsp90, histidine kinase, MutL)-type ATPase domain at its N-terminus. To formally assess the structure and function of Smchd1’s ATPase domain, we have generated recombinant proteins encompassing the predicted ATPase domain and the adjacent region. Here, we show that the Smchd1 N-terminal region exists as a monomer and adopts a conformation resembling that of monomeric full-length heat shock protein 90 (Hsp90) protein in solution, even though the two proteins share only ∼8% overall sequence identity. Despite being monomeric, the N-terminal region of Smchd1 exhibits ATPase activity, which can be antagonized by the reaction product, ADP, or the Hsp90 inhibitor, radicicol, at a nanomolar concentration. Interestingly, introduction of an analogous mutation to that identified in SMCHD1 of an FSHD patient compromised protein stability, suggesting a possible molecular basis for loss of protein function and pathogenesis. Together, these results reveal important structure–function characteristics of Smchd1 that may underpin its mechanistic action at the chromatin level.
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K-Ras4B membrane-anchored dimers in the cell. Dimerization can take place through helical (left) and beta-sheet (right) interfaces. The major (front) and minor (back) conformations are shown. For further details please see pp. 1719–1732. Image kindly provided by Ruth Nussinov. - PDF Icon PDF LinkFront Matter
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Research Article|
June 10 2016
The epigenetic regulator Smchd1 contains a functional GHKL-type ATPase domain
Kelan Chen;
Kelan Chen
*The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
†Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia
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Renwick C.J. Dobson;
Renwick C.J. Dobson
‡Biomolecular Interactions Centre and School of Biological Sciences, University of Canterbury, Christchurch 8042, New Zealand
§Bio21 Institute, Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia
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Isabelle S. Lucet;
Isabelle S. Lucet
*The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
†Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia
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Samuel N. Young;
Samuel N. Young
*The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
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F. Grant Pearce;
F. Grant Pearce
‡Biomolecular Interactions Centre and School of Biological Sciences, University of Canterbury, Christchurch 8042, New Zealand
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Marnie E. Blewitt;
Marnie E. Blewitt
1
*The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
†Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia
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James M. Murphy
*The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
†Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia
2To whom correspondence should be addressed (email jamesm@wehi.edu.au).
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Publisher: Portland Press Ltd
Received:
December 01 2015
Revision Received:
March 29 2016
Accepted:
April 08 2016
Accepted Manuscript online:
April 08 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (12): 1733–1744.
Article history
Received:
December 01 2015
Revision Received:
March 29 2016
Accepted:
April 08 2016
Accepted Manuscript online:
April 08 2016
Citation
Kelan Chen, Renwick C.J. Dobson, Isabelle S. Lucet, Samuel N. Young, F. Grant Pearce, Marnie E. Blewitt, James M. Murphy; The epigenetic regulator Smchd1 contains a functional GHKL-type ATPase domain. Biochem J 15 June 2016; 473 (12): 1733–1744. doi: https://doi.org/10.1042/BCJ20160189
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