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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites / genetics
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Catalytic Domain / genetics
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Co-Repressor Proteins
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Crystallography, X-Ray
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Histone Demethylases
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Histones / metabolism
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Humans
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Methylation
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Models, Molecular
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Monoamine Oxidase / chemistry
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Monoamine Oxidase / genetics
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Mutation, Missense
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Nerve Tissue Proteins / chemistry*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nucleosomes / metabolism*
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Oxidoreductases Acting on CH-NH Group Donors / chemistry
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Oxidoreductases Acting on CH-NH Group Donors / metabolism
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Oxidoreductases, N-Demethylating / chemistry*
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism
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Peptides / chemistry
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Polyamine Oxidase
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Protein Binding
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Protein Conformation
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Repressor Proteins / chemistry*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
Substances
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Co-Repressor Proteins
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DNA-Binding Proteins
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Histones
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Nerve Tissue Proteins
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Nucleosomes
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Peptides
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RCOR1 protein, human
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Recombinant Proteins
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Repressor Proteins
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Histone Demethylases
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Monoamine Oxidase
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KDM1A protein, human
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Oxidoreductases Acting on CH-NH Group Donors
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Oxidoreductases, N-Demethylating