Structure of the UHRF1 Tandem Tudor Domain Bound to a Methylated Non-histone Protein, LIG1, Reveals Rules for Binding and Regulation

Structure. 2019 Mar 5;27(3):485-496.e7. doi: 10.1016/j.str.2018.11.012. Epub 2019 Jan 10.


The protein UHRF1 is crucial for DNA methylation maintenance. The tandem Tudor domain (TTD) of UHRF1 binds histone H3K9me2/3 with micromolar affinity, as well as unmethylated linker regions within UHRF1 itself, causing auto-inhibition. Recently, we showed that a methylated histone-like region of DNA ligase 1 (LIG1K126me2/me3) binds the UHRF1 TTD with nanomolar affinity, permitting UHRF1 recruitment to chromatin. Here we report the crystal structure of the UHRF1 TTD bound to a LIG1K126me3 peptide. The data explain the basis for the high TTD-binding affinity of LIG1K126me3 and reveal that the interaction may be regulated by phosphorylation. Binding of LIG1K126me3 switches the overall structure of UHRF1 from a closed to a flexible conformation, suggesting that auto-inhibition is relieved. Our results provide structural insight into how UHRF1 performs its key function in epigenetic maintenance.

Keywords: DNA methylation; Tudor domain; UHRF1; X-ray crystallography; chromatin; lysine methylation; small-angle X-ray scattering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / metabolism
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins / chemistry*
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Crystallography, X-Ray
  • DNA Ligase ATP / chemistry*
  • DNA Ligase ATP / metabolism*
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Histones / metabolism
  • Humans
  • Methylation
  • Models, Molecular
  • Phosphorylation
  • Protein Conformation
  • Protein Domains
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / metabolism*


  • CCAAT-Enhancer-Binding Proteins
  • Histones
  • LIG1 protein, human
  • Arginine
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases
  • DNA Ligase ATP