title: A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation.
abstract: The methyltransferase activity of the trithorax group (TrxG) protein MLL1 found within its COMPASS (complex associated with SET1)-like complex is allosterically regulated by a four-subunit complex composed of WDR5, RbBP5, Ash2L, and DPY30 (also referred to as WRAD). We report structural evidence showing that in WRAD, a concave surface of the Ash2L SPIa and ryanodine receptor (SPRY) domain binds to a cluster of acidic residues, referred to as the D/E box, in RbBP5. Mutational analysis shows that residues forming the Ash2L/RbBP5 interface are important for heterodimer formation, stimulation of MLL1 catalytic activity, and erythroid cell terminal differentiation. We also demonstrate that a phosphorylation switch on RbBP5 stimulates WRAD complex formation and significantly increases KMT2 (lysine [K] methyltransferase 2) enzyme methylation rates. Overall, our findings provide structural insights into the assembly of the WRAD complex and point to a novel regulatory mechanism controlling the activity of the KMT2/COMPASS family of lysine methyltransferases.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Pamela
authors.initials: P
authors.lastname: Zhang
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Chandra-Prakash
authors.initials: CP
authors.lastname: Chaturvedi
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Veronique
authors.initials: V
authors.lastname: Tremblay
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Myriam
authors.initials: M
authors.lastname: Cramet
authors.affiliation: Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Brunzelle
authors.affiliation: Life Sciences Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8L6, Canada;
authors.forename: Marjorie
authors.initials: M
authors.lastname: Brand
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; jean-francois.couture@uottawa.ca.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Couture
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003460:Crystallization; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D041905:Erythroid Cells / Q000166:cytology / Q000201:enzymology; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D008780:Methyltransferases / Q000378:metabolism; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
chemical_list: C120115:Ash2l protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C557020:RBBP5 protein, mouse; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
keywords: COMPASS; chromatin; epigenetics; histone H3 Lys4; methylation