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Fine‐tuning the stimulation of MLL1 methyltransferase activity by a histone H3‐based peptide mimetic
Author(s) -
Avdic Vanja,
Zhang Pamela,
Lanouette Sylvain,
Voronova Anastassia,
Skerjanc Ilona,
Couture JeanFrancois
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-171959
Subject(s) - histone h3 , histone methyltransferase , methyltransferase , methylation , acetylation , moiety , histone methylation , histone , chemistry , peptide , epigenetics , biochemistry , microbiology and biotechnology , biology , stereochemistry , dna methylation , gene expression , gene
The SETI 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.—Avdic, V., Zhang, P., Lanouette, S., Voronova, A., Skerjanc, I., Couture, J.‐F. Fine‐tuning the stimulation of MLL1 methyltransferase activity by a histone H3‐based peptide mimetic. FASEB J. 25, 960–967 (2011). www.fasebj.org