Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid–binding residues
Kelan Chen, Richard W. Birkinshaw, Alexandra D. Gurzau, Iromi Wanigasuriya, Ruoyun Wang, Megan Iminitoff, Jarrod J. Sandow, Samuel N. Young, Patrick J. Hennessy, Tracy A. Willson, Denise A. Heckmann, Andrew I. Webb, Marnie E. Blewitt, Peter E. Czabotar, James M. Murphy
Abstract
Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL-type, rather than an ABC-type ATPase domain at its N terminus. The hinge domain has been previously implicated in chromatin association; however, the underlying mechanism involved and the basis for SMCHD1 homodimerization are unclear. Here, we used x-ray crystallography to solve the three-dimensional structure of the Smchd1 hinge domain. Together with structure-guided mutagenesis, we defined structural features of the hinge domain that participated in homodimerization and nucleic acid binding, and we identified a functional hotspot required for chromatin localization in cells. This structure provides a template for interpreting the mechanism by which patient polymorphisms within the SMCHD1 hinge domain could compromise function and lead to facioscapulohumeral muscular dystrophy.