Molecular basis for the methylation specificity of ATXR5 for histone H3.

Abstract

In plants, the histone H3.1 lysine 27 (H3K27) mono-methyltransferases ARABIDOPSIS TRITHORAX RELATED PROTEIN 5 and 6 (ATXR5/6) regulate heterochromatic DNA replication and genome stability. Our initial studies showed that ATXR5/6 discriminate between histone H3 variants and preferentially methylate K27 on H3.1. In this study, we report three regulatory mechanisms contributing to the specificity of ATXR5/6. First, we show that ATXR5 preferentially methylates the R/F-K*-S/C-G/A-P/C motif with striking preference for hydrophobic and aromatic residues in positions flanking this core of five amino acids. Second, we demonstrate that post-transcriptional modifications of residues neighboring K27 that are typically associated with actively transcribed chromatin are detrimental to ATXR5 activity. Third, we show that ATXR5 PHD domain employs a narrow binding pocket to selectively recognize unmethylated K4 of histone H3. Finally, we demonstrate that deletion or mutation of the PHD domain reduces the catalytic efficiency (kcat/Km of AdoMet) of ATXR5 up to 58-fold, highlighting the multifunctional nature of ATXR5 PHD domain. Overall, our results suggest that several molecular determinants regulate ATXR5/6 methyltransferase activity and epigenetic inheritance of H3.1 K27me1 mark in plants.

• Authors: Elisa Bergamin, Sabina Sarvan, Josée Malette, Mohammad S Eram, Sylvain Yeung, Vanessa Mongeon, Monika Joshi, Joseph S Brunzelle, Scott D Michaels, Alexandre Blais, Masoud Vedadi, Jean-François Couture
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 45 Issue 11 Pg. 6375-6387 (Jun 20 2017) ISSN: 1362-4962 [Electronic] England
• PMID: 28383693 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Arabidopsis Proteins
• Histones
• ATXR5 protein, Arabidopsis
• Methyltransferases

Topics

• Amino Acid Motifs
• Arabidopsis (enzymology)
• Arabidopsis Proteins (chemistry, physiology)
• Catalytic Domain
• Crystallography, X-Ray
• Gene Expression Regulation, Plant
• Histones (chemistry)
• Hydrogen Bonding
• Hydrophobic and Hydrophilic Interactions
• Kinetics
• Methylation
• Methyltransferases (chemistry, physiology)
• Models, Molecular
• Protein Binding
• Protein Processing, Post-Translational
• Substrate Specificity