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.

含有 1 的染色体柔性铰链结构域的结构维持 (SMCHD1) 是一种表观遗传调节器，其中多态性导致人类发育障碍、Bosma arhinia micropthalmia 综合征和退行性疾病、面肩肱型肌营养不良症。SMCHD1 被认为是非经典 SMC 家族成员，因为它的铰链域是 C 端，因为它是同源二聚体而不是异源二聚体，并且因为 SMCHD1 在其 N 末端包含一个 GHKL 型，而不是一个 ABC 型 ATPase 结构域。铰链域以前曾与染色质关联有关。然而，所涉及的潜在机制和 SMCHD1 同源二聚化的基础尚不清楚。在这里，我们使用 X 射线晶体学来解决 Smchd1 铰链域的三维结构。与结构引导的诱变一起，我们定义了参与同源二聚化和核酸结合的铰链结构域的结构特征，并确定了细胞中染色质定位所需的功能热点。这种结构提供了一个模板，用于解释 SMCHD1 铰链域内的患者多态性可能损害功能并导致面肩肱型肌营养不良症的机制。