@article{e9782228ee25401a853d6488ac5c8e08,
title = "Crystal Structure of the LSD1/CoREST Histone Demethylase Bound to Its Nucleosome Substrate",
abstract = "LSD1 (lysine specific demethylase; also known as KDM1A), the first histone demethylase discovered, regulates cell-fate determination and is overexpressed in multiple cancers. LSD1 demethylates histone H3 Lys4, an epigenetic mark for active genes, but requires the CoREST repressor to act on nucleosome substrates. To understand how an accessory subunit (CoREST) enables a chromatin enzyme (LSD1) to function on a nucleosome and not just histones, we have determined the crystal structure of the LSD1/CoREST complex bound to a 191-bp nucleosome. We find that the LSD1 catalytic domain binds extranucleosomal DNA and is unexpectedly positioned 100 {\AA} away from the nucleosome core. CoREST makes critical contacts with both histone and DNA components of the nucleosome, explaining its essential function in demethylating nucleosome substrates. Our studies also show that the LSD1(K661A) frequently used as a catalytically inactive mutant in vivo (based on in vitro peptide studies) actually retains substantial H3K4 demethylase activity on nucleosome substrates.",
author = "Kim, {Sang Ah} and Jiang Zhu and Neela Yennawar and Priit Eek and Song Tan",
note = "Funding Information: We gratefully acknowledge Michael Doyle, Gabe Epstein, Jeffrey Hall, Maxwell Kruse, Lauren McCarl, Kevin Thyne, and Bryan Tornabene for superb technical assistance; James Johnston, Turner Pecen, and Victoria Spadafora for reagent preparation; Blaine Bartholomew and Matthew Jennings for early contributions to this project; and Rob McGinty, other members of the Tan laboratory, and the Penn State Center for Eukaryotic Gene Regulation for suggestions and discussions. We also thank Beno{\^i}t Laurent and Yang Shi for sharing reagents. We thank the staff of APS beamlines 24-ID-C and 24-ID-E for their help during synchrotron data collection using NE-CAT beamlines (GM124165), a Pilatus detector (RR029205), and an Eiger detector (OD021527) at the APS (DE-AC02-06CH11357). This work was supported by Estonian Research Council grant PUTJD906 to P.E. and by NIH NIGMS grants R01 GM088236, R01 GM111651, and R35 GM127034 to S.T. S.-A.K. performed biochemical, crystallization, and crystallographic experiments. J.Z. performed biochemical experiments. S.-A.K. J.Z. and N.Y. solved and refined the LSD1/CoREST/191-bp nucleosome crystal structure. P.E. improved the LSD1/CoREST/189-bp nucleosome crystal molecular replacement model. S.T. conceived the experiments, provided reagents, supervised the project, wrote the manuscript, and secured funding. The authors declare no competing interests. Funding Information: We gratefully acknowledge Michael Doyle, Gabe Epstein, Jeffrey Hall, Maxwell Kruse, Lauren McCarl, Kevin Thyne, and Bryan Tornabene for superb technical assistance; James Johnston, Turner Pecen, and Victoria Spadafora for reagent preparation; Blaine Bartholomew and Matthew Jennings for early contributions to this project; and Rob McGinty, other members of the Tan laboratory, and the Penn State Center for Eukaryotic Gene Regulation for suggestions and discussions. We also thank Beno{\^i}t Laurent and Yang Shi for sharing reagents. We thank the staff of APS beamlines 24-ID-C and 24-ID-E for their help during synchrotron data collection using NE-CAT beamlines (GM124165), a Pilatus detector (RR029205), and an Eiger detector (OD021527) at the APS (DE-AC02-06CH11357). This work was supported by Estonian Research Council grant PUTJD906 to P.E. and by NIH NIGMS grants R01 GM088236 , R01 GM111651 , and R35 GM127034 to S.T. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jun,
day = "4",
doi = "10.1016/j.molcel.2020.04.019",
language = "English (US)",
volume = "78",
pages = "903--914.e4",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}