title: Nucleosome Binding Alters the Substrate Bonding Environment of Histone H3 Lysine 36 Methyltransferase NSD2.
abstract: Nuclear receptor-binding SET domain protein 2 (NSD2) is a histone H3 lysine 36 (H3K36)-specific methyltransferase enzyme that is overexpressed in a number of cancers, including multiple myeloma. NSD2 binds to S-adenosyl-l-methionine (SAM) and nucleosome substrates to catalyze the transfer of a methyl group from SAM to the ε-amino group of histone H3K36. Equilibrium binding isotope effects and density functional theory calculations indicate that the SAM methyl group is sterically constrained in complex with NSD2, and that this steric constraint is released upon nucleosome binding. Together, these results show that nucleosome binding to NSD2 induces a significant change in the chemical environment of enzyme-bound SAM.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
authors.forename: Myles B
authors.initials: MB
authors.lastname: Poulin
authors.affiliation: Biological Sciences, Platform Technology and Science, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Schneck
authors.affiliation: Biological Sciences, Platform Technology and Science, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Rosalie E
authors.initials: RE
authors.lastname: Matico
authors.affiliation: Biological Sciences, Platform Technology and Science, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Wangfang
authors.initials: W
authors.lastname: Hou
authors.affiliation: Biological Sciences, Platform Technology and Science, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McDevitt
authors.affiliation: Biological Sciences, Platform Technology and Science, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Holbert
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461, United States.
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008962:Models, Theoretical; D009707:Nucleosomes / Q000737:chemistry*; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry*; D012436:S-Adenosylmethionine / Q000737:chemistry*
chemical_list: D009707:Nucleosomes; D012097:Repressor Proteins; D012436:S-Adenosylmethionine; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human