title: Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase.
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.
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Maojun
authors.initials: M
authors.lastname: Yang
authors.forename: Christian B
authors.initials: CB
authors.lastname: Gocke
authors.forename: Xuelian
authors.initials: X
authors.lastname: Luo
authors.forename: Dominika
authors.initials: D
authors.lastname: Borek
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.forename: Mischa
authors.initials: M
authors.lastname: Machius
authors.forename: Zbyszek
authors.initials: Z
authors.lastname: Otwinowski
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yu
mesh_terms: D001665:Binding Sites / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D056970:Co-Repressor Proteins; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000235:genetics; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000737:chemistry / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000097667:Polyamine Oxidase
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D056466:Histone Demethylases; D006657:Histones; D008995:Monoamine Oxidase; D009419:Nerve Tissue Proteins; D009707:Nucleosomes; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010089:Oxidoreductases, N-Demethylating; D010455:Peptides; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000097667:Polyamine Oxidase; C121019:RCOR1 protein, human; C495195:KDM1A protein, human