title: LSD2/KDM1B and its cofactor NPAC/GLYR1 endow a structural and molecular model for regulation of H3K4 demethylation.
abstract: Dynamic regulation of histone methylation represents a fundamental epigenetic mechanism underlying eukaryotic gene regulation, yet little is known about how the catalytic activities of histone demethylases are regulated. Here, we identify and characterize NPAC/GLYR1 as an LSD2/KDM1b-specific cofactor that stimulates H3K4me1 and H3K4me2 demethylation. We determine the crystal structures of LSD2 alone and LSD2 in complex with the NPAC linker region in the absence or presence of histone H3 peptide, at resolutions of 2.9, 2.0, and 2.25 Å, respectively. These crystal structures and further biochemical characterization define a dodecapeptide of NPAC (residues 214-225) as the minimal functional unit for its cofactor activity and provide structural determinants and a molecular mechanism underlying the intrinsic cofactor activity of NPAC in stimulating LSD2-catalyzed H3K4 demethylation. Thus, these findings establish a model for how a cofactor directly regulates histone demethylation and will have a significant impact on our understanding of catalytic-activity-based epigenetic regulation.
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine and Department of Biological Chemistry & Molecular Pharmacology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Fang
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Dong
authors.forename: Di
authors.initials: D
authors.lastname: Hu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Barbera
authors.forename: Erin A
authors.initials: EA
authors.lastname: Clark
authors.forename: Jian
authors.initials: J
authors.lastname: Fang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Pinchao
authors.initials: P
authors.lastname: Mei
authors.forename: Michael
authors.initials: M
authors.lastname: Rutenberg
authors.forename: Ze
authors.initials: Z
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Youwei
authors.initials: Y
authors.lastname: Xu
authors.forename: Huirong
authors.initials: H
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Simon
authors.forename: Qiongjie
authors.initials: Q
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Mark P
authors.initials: MP
authors.lastname: Marynick
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Li
authors.forename: Haojie
authors.initials: H
authors.lastname: Lu
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Robert E
authors.initials: RE
authors.lastname: Kingston
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
authors.forename: Yujiang Geno
authors.initials: YG
authors.lastname: Shi
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D003067:Coenzymes / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004795:Enzyme Stability; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D003067:Coenzymes; D006657:Histones; D010455:Peptides; D000429:Alcohol Oxidoreductases; C020830:glyoxylate reductase; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine