Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase

Mol Cell. 2006 Aug 4;23(3):377-87. doi: 10.1016/j.molcel.2006.07.012.

Abstract

Histone methylation regulates diverse chromatin-templated processes, including transcription. Many transcriptional corepressor complexes contain lysine-specific demethylase 1 (LSD1) and CoREST that collaborate to demethylate mono- and dimethylated H3-K4 of nucleosomes. Here, we report the crystal structure of the LSD1-CoREST complex. LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain. LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface. CoREST SANT2 interacts with DNA. Disruption of the SANT2-DNA interaction diminishes CoREST-dependent demethylation of nucleosomes by LSD1. The shape and dimension of LSD1-CoREST suggest its bivalent binding to nucleosomes, allowing efficient H3-K4 demethylation. This spatially separated, multivalent nucleosome binding mode may apply to other chromatin-modifying enzymes that generally contain multiple nucleosome binding modules.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites / genetics
  • Catalytic Domain / genetics
  • Co-Repressor Proteins
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Histone Demethylases
  • Histones / metabolism
  • Humans
  • Methylation
  • Models, Molecular
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / genetics
  • Mutation, Missense
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nucleosomes / metabolism*
  • Oxidoreductases Acting on CH-NH Group Donors / chemistry
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Oxidoreductases, N-Demethylating / chemistry*
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Peptides / chemistry
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Repressor Proteins / chemistry*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Histones
  • Nerve Tissue Proteins
  • Nucleosomes
  • Peptides
  • RCOR1 protein, human
  • Recombinant Proteins
  • Repressor Proteins
  • Histone Demethylases
  • Monoamine Oxidase
  • KDM1A protein, human
  • Oxidoreductases Acting on CH-NH Group Donors
  • Oxidoreductases, N-Demethylating
  • polyamine oxidase

Associated data

  • PDB/2IW5