Histone modification is a key mechanism for regulating chromatin structure and function. It is a dynamic process that is tightly regulated by a variety of enzymes and errors in this process can lead to diseases such as cancer. KDM5A is lysine demethylase that removes methyl groups from tri-, di- and mono-methylated lysine 4 residues of histone H3 (H3K4me3/2/1). This multi-domain enzyme contains three plant homeodomain (PHD) domains, traditionally recognised as chromatin recruitment domains. The first PHD domain (PHD1) of KDM5A is able to bind N-terminal region of H3 and enhance the demethylase activity of KDM5A via an allosteric mechanism. However, it is unknown what the exact mechanism of this allosteric communication is. Here we show that upon PHD1 occupation a decrease in the <i>K</i><sub>m</sub> occurs, which suggests improved binding of substrate to the catalytic domain. We also show what the effect of different post-translational modifications of the N-terminal of H3 has on binding to the PHD1 domain and to the catalytic enhancement of KDM5A. Finally, using NMR we have been able to identify residues of the PHD1 domain that interact with the H3 histone tail and residues that could potentially be important in allosteric communication. Given the role of KDM5A in various cancers, insights into this allosteric control could lead to opportunities to develop small molecule allosteric inhibitors.

Allosteric control of histone demethylase KDM5A

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.