The structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) protein is an epigenetic regulator involved in the maintaining higher-order chromatin structures for gene regulation. SMCHD1 polymorphisms cause several human developmental disorders and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is the only known mammalian SMC hinge domain protein that forms SMC homodimers, with all other eukaryotic SMC proteins heterodimerising with other family members. SMCHD1 chromatin interactions are facilitated by the hinge domain, however the underlying mechanism and the basis for SMCHD1 homodimerisation rather than the heterodimerisation, were unclear.
Here, we describe the first structure of the SMCHD1 hinge domain by X-ray crystallography. This required solving a challenging de novo phasing problem through a combination of multiple single-wavelength anomalous dispersion experiments and molecular replacement, that was hindered by low resolution phase information and poor homology models. This structure guided our mutagenesis studies that define the structural features of the hinge domain required for homodimerization, nucleic acid binding and identify a functional hotspot that recruits SMCHD1 to chromatin in cells. These new insights inform how SMCHD1 hinge domain polymorphisms could compromise function and lead to facioscapulohumeral muscular dystrophy.