Structural Maintenance of Chromosomes flexible Hinge Domain-containing 1 (Smchd1) is a non-canonical SMC protein that plays critical roles in epigenetic regulation including X chromosome inactivation, genomic imprinting and regulation of autosomal gene expression. Recently, mutations in SMCHD1 have been implicated in facioscapulohumeral muscular dystrophy (FSHD) and a rare craniofacial disorder called Bosma arhinia microphthalmia syndrome (BAM). While the importance of SMCHD1 is well-described, how SMCHD1 protein functions at the molecular level to mediate epigenetic control is still unclear.
We have performed structural-functional characterisation of the two recognisable domains of Smchd1, namely the SMC hinge domain that is responsible for nucleic acid binding and the putative GHKL ATPase domain. We demonstrated that the hinge domain of Smchd1 assembles into an unconventional dimeric arrangement flanked by intermolecular coiled-coils. Furthermore, we showed the N-terminal region of Smchd1 that encapsulates the ATPase domain grossly resembles the crystal structure of full-length Hsp90 protein. Importantly, we found the ATPase domain of Smchd1 is catalytically active. Therefore, similar to Hsp90’s ATP-binding dependent conformational changes, we envisage that Smchd1 dimer may undergo energy-dependent conformational changes to engage with chromatin. Additionally, ongoing characterisation of recombinant proteins incorporating patient-derived SMCHD1 mutations have provided potential explanations for the underlying pathogenesis. Finally, our study has formed the basis of exploring activation of SMCHD1 as a potential therapeutic treatment for FSHD.