4X8N : Crystal structure of Ash2L SPRY domain in complex with phosphorylated RbBP5

  • Pamela Zhang (Contributor)
  • Chandra Prakash Chaturvedi (Contributor)
  • Joseph S. Brunzelle (Contributor)
  • Georgios Skiniotis (Contributor)
  • Marjorie Brand (Contributor)
  • Ali Shilatifard (Contributor)
  • Jean Fran├žois Couture (Contributor)



Experimental Technique/Method:X-RAY DIFFRACTION
Classification:PROTEIN BINDING
Release Date:2015-01-28
Deposition Date:2014-12-10
Revision Date:2017-09-06
Molecular Weight:21671.32
Macromolecule Type:Protein
Residue Count:191
Atom Site Count:1496

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.
Date made available2015

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