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Investigation COMMUNICATIONA phosphorylation mTOR Modulator Formulation switch on RbBP5 regulates histone H3 Lys4 methylationPamela Zhang,1 Chandra-Prakash Chaturvedi,two,three Veronique Tremblay,1 Myriam Cramet,1 Joseph S. Brunzelle,4 Georgios Skiniotis,5,six Marjorie Brand,two,three Ali Shilatifard,7 and Jean-Francois Couture1 Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; 2The Sprott Center for Stem Cell Research, Regenerative Medicine Plan, Ottawa Hospital Investigation Institute, Ottawa, Ontario K1H 8L6, Canada; 3Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8L6, Canada; 4Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA; 5Life Sciences Institute, 6Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA; 7Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois 60611, USAThe methyltransferase activity on the trithorax group (TrxG) protein MLL1 located inside its COMPASS (complicated related 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 proof 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 evaluation 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 considerably increases KMT2 (lysine [K] methyltransferase 2) enzyme methylation rates. General, our findings present structural insights into the assembly of your WRAD complicated and point to a novel regulatory mechanism controlling the activity from the KMT2/COMPASS family members of lysine methyltransferases.Supplemental P2Y1 Receptor Antagonist custom synthesis material is readily available for this article. Received October 27, 2014; revised version accepted December 15, 2014.The methyltransferase activity in the trithorax group (TrxG) protein MLL1 too because the other members from the KMT2 (lysine [K] methyltransferase two) family members found inside COMPASS (complicated linked with SET1) catalyzes the[Keywords: COMPASS; chromatin; epigenetics; histone H3 Lys4; methylation] Corresponding author: [email protected] Write-up is online at http://genesdev.org/cgi/doi/10.1101/gad.254.