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Illuminating dimerization
Proteins of the SMC family are chromosomal organizers involved in sister chromatid cohesion, chromosome condensation, and DNA repair. Unlike other eukaryotic family members, SMCHD1 forms homodimers, rather than heterodimers, and has a distinct domain architecture. Dysregulation of SMCHD1 function results in a form of muscular dystrophy and a developmental disorder. Chen et al. solved the x-ray crystal structure of the Smchd1 hinge domain, which is important for homodimerization and nucleic acid binding. Site-directed mutagenesis studies identified critical residues involved in SMCHD1 function in cells. Together, these data suggest how mutations in the SMCHD1 hinge domain contribute to human disease.
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.
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