4X8N

Crystal structure of Ash2L SPRY domain in complex with phosphorylated RbBP5

Summary for 4X8N

• Entry DOI: 10.2210/pdb4x8n/pdb
• Related: 4X8P
• Descriptor: Set1/Ash2 histone methyltransferase complex subunit ASH2, Retinoblastoma-binding protein 5 (3 entities in total)
• Functional Keywords: histone, mll1, chromatin, epigenetics, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 21671.32

Authors

Zhang, P.,Chaturvedi, C.P.,Brunzelle, J.S.,Skiniotis, G.,Brand, M.,Shilatifard, A.,Couture, J.-F. (deposition date: 2014-12-10, release date: 2015-01-28, Last modification date: 2024-10-23)

Primary citation

Zhang, P.,Chaturvedi, C.P.,Tremblay, V.,Cramet, M.,Brunzelle, J.S.,Skiniotis, G.,Brand, M.,Shilatifard, A.,Couture, J.F.
A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation.
Genes Dev., 29:123-128, 2015

PubMed 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.

PubMed: 25593305
DOI: 10.1101/gad.254870.114

Experimental method

X-RAY DIFFRACTION (2.1 Å)