A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• The COMPASS-like complex, including the MLL1 methyltransferase, is regulated by the WRAD complex.
• Understanding WRAD complex assembly and regulation is crucial for comprehending KMT2 enzyme activity.

Purpose of the Study:

• To elucidate the structural basis of WRAD complex formation.
• To investigate the regulatory mechanisms controlling MLL1 methyltransferase activity.

Main Methods:

• X-ray crystallography to determine the structure of the WRAD complex.
• Site-directed mutagenesis to analyze protein-protein interactions.
• Biochemical assays to measure methyltransferase activity.

Main Results:

• Structural data reveals Ash2L's SPRY domain binding to RbBP5's D/E box within the WRAD complex.
• Mutations at the Ash2L/RbBP5 interface disrupt heterodimer formation, MLL1 activity, and erythroid differentiation.
• RbBP5 phosphorylation enhances WRAD complex formation and KMT2 methylation rates.

Conclusions:

• The findings provide structural insights into WRAD complex assembly.
• A novel regulatory mechanism involving RbBP5 phosphorylation controls KMT2/COMPASS family activity.