A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

Pamela Zhang, Chandra Prakash Chaturvedi, Veronique Tremblay, Myriam Cramet, Joseph S. Brunzelle, Georgios Skiniotis, Marjorie Brand, Ali Shilatifard, Jean François Couture*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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, andDPY30 (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 stimulatesWRAD 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.

Original languageEnglish (US)
Pages (from-to)123-128
Number of pages6
JournalGenes and Development
Volume29
Issue number2
DOIs
StatePublished - Jan 15 2015

Keywords

  • COMPASS
  • Chromatin
  • Epigenetics
  • Histone H3 Lys4
  • Methylation

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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