A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

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 sho...

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Bibliographic Details
Published in:Genes & development 2015-01, Vol.29 (2), p.123-128
Main Authors: Zhang, Pamela, Chaturvedi, Chandra-Prakash, Tremblay, Veronique, Cramet, Myriam, Brunzelle, Joseph S, Skiniotis, Georgios, Brand, Marjorie, Shilatifard, Ali, Couture, Jean-François
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Cell Line, Tumor
Crystallization
DNA Mutational Analysis
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - metabolism
Enzyme Activation - genetics
Erythroid Cells - cytology
Erythroid Cells - enzymology
Histone-Lysine N-Methyltransferase - metabolism
Histones - metabolism
Methylation - drug effects
Methyltransferases - metabolism
Models, Molecular
Myeloid-Lymphoid Leukemia Protein - metabolism
Nuclear Proteins - chemistry
Nuclear Proteins - metabolism
Phosphorylation
Protein Binding
Protein Structure, Tertiary
Research Communication
Transcription Factors - chemistry
Transcription Factors - metabolism
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.254870.114