The epigenetic regulator Smchd1 contains a functional GHKL-type ATPase domain
- Author(s)
- Chen, K; Dobson, RC; Lucet, I; Young, SN; Pearce, FG; Blewitt, ME; Murphy, JM;
- Details
- Publication Year 2016-04-08,Volume 473,Issue #6,Page 733-742
- Journal Title
- Biochem J
- Publication Type
- Journal Article
- Abstract
- 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 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 antagonised 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.
- Publisher
- Portland Press
- Research Division(s)
- Molecular Genetics Of Cancer
- PubMed ID
- 27059856
- Publisher's Version
- https://doi.org/10.1042/BCJ20160189
- NHMRC Grants
- NHMRC/1045936, NHMRC/1110206, NHMRC/1105754,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-04-28 02:07:00
Last Modified: 2018-03-08 03:50:11