Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) plays important roles in epigenetic silencing and normal mammalian development. Recently, heterozygous mutations in SMCHD1 were found to contribute to two distinct conditions: facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia micropthalmia syndrome (BAMS). Despite SMCHD1’s essential role in epigenetic regulation, its atomic structure and the molecular mechanisms underlying its function in both a healthy and diseased state remain to be elucidated.
SMCHD1 is considered a non-canonical SMC family member due to its C-terminal hinge domain that homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL- rather than ABC- type ATPase domain at its N-terminus. Previous studies have implicated the hinge domain in chromatin association, although in the absence of high-resolution structural information. The underlying mechanism and the basis for SMCHD1 homodimerisation rather than heterodimerisation, which is typical of eukaryotic SMC proteins, have remained unclear. We used X-ray crystallography to solve the first three-dimensional structure of the Smchd1 hinge domain. Together with structure-guided mutagenesis, we have defined structural features of the hinge domain that participate in homodimerisation and nucleic acid binding, and identified a functional hotspot required for chromatin localisation in cells. This structure provides a template for interpreting the mechanism by which patient mutations within the SMCHD1 hinge domain could compromise function and lead to disease.