Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid-binding residues

Sci Signal. 2020 Jun 16;13(636):eaaz5599. doi: 10.1126/scisignal.aaz5599.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosomal Proteins, Non-Histone / chemistry*
  • Chromosomal Proteins, Non-Histone / genetics
  • Crystallography, X-Ray
  • Mice
  • Nucleic Acids / chemistry
  • Nucleic Acids / metabolism
  • Protein Domains
  • Protein Multimerization*
  • Protein Structure, Quaternary
  • Siblings

Substances

  • Chromosomal Proteins, Non-Histone
  • Nucleic Acids
  • SmcHD1 protein, mouse