Fine-tuning the stimulation of MLL1 methyltransferase activity by a histone H3-based peptide mimetic.
The SET1 family of methyltransferases carries out the bulk of histone H3 Lys-4 methylation in vivo. One of the common features of this family is the regulation of their methyltransferase activity by a tripartite complex composed of WDR5, RbBP5, and Ash2L. To selectively probe the role of the SET1 family of methyltransferases, we have developed a library of histone H3 peptide mimetics and report herein the characterization of an Nα acetylated form of histone H3 peptide (NαH3). Binding and inhibition studies reveal that the addition of an acetyl moiety to the N terminus of histone H3 significantly enhances its binding to WDR5 and prevents the stimulation of MLL1 methyltransferase activity by the WDR5-RbBP5-Ash2L complex. The crystal structure of NαH3 in complex with WDR5 reveals that a high-affinity hydrophobic pocket accommodates the binding of the acetyl moiety. These results provide the structural basis to control WDR5-RbBP5-Ash2L-MLL1 activity and a tool to manipulate stem cell differentiation programs.
University of Ottawa, Ottawa Institute of Systems Biology, 451 Smyth Rd., Roger Guindon Hall, Ottawa, ON K1H 8M5, Canada.
Vanja
V
Avdic
Pamela
P
Zhang
Sylvain
S
Lanouette
Anastassia
A
Voronova
Ilona
I
Skerjanc
Jean-Francois
JF
Couture
D000107:Acetylation; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003461:Crystallography; D019175:DNA Methylation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D057890:Epigenomics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008956:Models, Chemical; D018716:Molecular Mimicry; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D009707:Nucleosomes / Q000502:physiology; D019151:Peptide Library; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D014157:Transcription Factors / Q000378:metabolism
C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D009707:Nucleosomes; D019151:Peptide Library; C470552:RBBP5 protein, human; D014157:Transcription Factors; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase