Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin

Nat Struct Mol Biol. 2011 Jun 12;18(7):777-82. doi: 10.1038/nsmb.2070.

Abstract

Accurate read-out of chromatin modifications is essential for eukaryotic life. Mutations in the gene encoding X-linked ATRX protein cause a mental-retardation syndrome, whereas wild-type ATRX protein targets pericentric and telomeric heterochromatin for deposition of the histone variant H3.3 by means of a largely unknown mechanism. Here we show that the ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. In vivo experiments show this combinatorial readout is required for ATRX localization, with recruitment enhanced by a third interaction through heterochromatin protein-1 (HP1) that also recognizes trimethylated Lys9. The cooperation of ATRX ADD domain and HP1 in chromatin recruitment results in a tripartite interaction that may span neighboring nucleosomes and illustrates how the 'histone-code' is interpreted by a combination of multivalent effector-chromatin interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Helicases / chemistry*
  • DNA Helicases / metabolism
  • DNA Helicases / physiology
  • Heterochromatin / chemistry
  • Heterochromatin / metabolism*
  • Histone Code
  • Histones / chemistry
  • Histones / metabolism*
  • Methylation
  • Nuclear Magnetic Resonance, Biomolecular
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology
  • X-linked Nuclear Protein

Substances

  • Chromosomal Proteins, Non-Histone
  • Heterochromatin
  • Histones
  • Nuclear Proteins
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein

Associated data

  • PDB/2LBM