Mechanism of Crosstalk between the LSD1 Demethylase and HDAC1 Deacetylase in the CoREST Complex
Yun Song,
Lisbeth Dagil,
Louise Fairall,
Naomi Robertson,
Mingxuan Wu,
T.J. Ragan,
Christos G. Savva,
Almutasem Saleh,
Nobuhiro Morone,
Micha B.A. Kunze,
Andrew G. Jamieson,
Philip A. Cole,
D. Flemming Hansen,
John W.R. Schwabe
Affiliations
Yun Song
Leicester Institute of Chemical and Molecular Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
Lisbeth Dagil
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
Louise Fairall
Leicester Institute of Chemical and Molecular Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
Naomi Robertson
Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, UK
Mingxuan Wu
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
T.J. Ragan
Leicester Institute of Chemical and Molecular Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
Christos G. Savva
Leicester Institute of Chemical and Molecular Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
Almutasem Saleh
Leicester Institute of Chemical and Molecular Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK
Nobuhiro Morone
MRC-Toxicology Unit, University of Cambridge, University Road, Leicester LE1 7RH, UK
Micha B.A. Kunze
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
Andrew G. Jamieson
Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, UK
Philip A. Cole
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
D. Flemming Hansen
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK; Corresponding author
John W.R. Schwabe
Leicester Institute of Chemical and Molecular Biology, Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 7RH, UK; Corresponding author
Summary: The transcriptional corepressor complex CoREST is one of seven histone deacetylase complexes that regulate the genome through controlling chromatin acetylation. The CoREST complex is unique in containing both histone demethylase and deacetylase enzymes, LSD1 and HDAC1, held together by the RCOR1 scaffold protein. To date, it has been assumed that the enzymes function independently within the complex. Now, we report the assembly of the ternary complex. Using both structural and functional studies, we show that the activity of the two enzymes is closely coupled and that the complex can exist in at least two distinct states with different kinetics. Electron microscopy of the complex reveals a bi-lobed structure with LSD1 and HDAC1 enzymes at opposite ends of the complex. The structure of CoREST in complex with a nucleosome reveals a mode of chromatin engagement that contrasts with previous models. : Using a real-time NMR assay, Song et al. characterize crosstalk between LSD1 and HDAC1 in the CoREST complex. Activation or inhibition of one enzyme strongly affects activity of the other. Electron microscopy studies of the complex reveal a bi-lobed structure with implications for the mode of interaction with nucleosomes. Keywords: CoREST complex, RCOR1, HDAC1, LSD1, KDM1A, nucleosome, histone deacetylase, lysine demethylase
