Evaluation of Jumonji C lysine demethylase substrate preference to guide identification of in vitro substrates

Summary The KDM5/JARID1 sub-family are 2-oxoglutarate and Fe(II)-dependent lysine-specific histone demethylases that are characterized by their Jumonji catalytic domains. The KDM5 family is known to remove tri-/di-methyl modifications from lysine-4 of histone H3 (i.e., H3-K4me2/3), a mark associated with active gene expression. As a result, studies to date have revolved around the influence of KDM5 on disease through their ability to regulate H3-K4me2/3. Recent evidence demonstrates that KDM5 may influence disease beyond H3-K4 demethylation, making it critical to further investigate KDM5-mediated demethylation of non-histone proteins. To help identify potential non-histone substrates for the KDM5 family, we developed a library of 180 permutated peptide substrates (PPS), with sequences that are systematically altered from the wild-type H3-K4me3 substrate. From this library, we characterized recombinant KDM5A/B/C/D substrate preference and developed recognition motifs for each KDM5 demethylase. The recognition motifs developed were used to predict potential substrates for KDM5A/B/C/D and profiled to generate a list of high-ranking and medium/low-ranking substrates for further in vitro validation. Through this approach, we identified 66 high-ranking substrates in which KDM5 demethylases displayed significant in vitro activity towards.

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Evaluation of Jumonji C lysine demethylase substrate preference to guide identification of in vitro substrates

Cited by 3 publications

References 24 publications

PeSA 2.0: A software tool for peptide specificity analysis implementing positive and negative motifs and motif-based peptide scoring

PeSA 2.0: A software tool for peptide specificity analysis implementing positive and negative motifs and motif-based peptide scoring

Emergent properties of the lysine methylome reveal regulatory roles via protein interactions and histone mimicry

Characterization of KDM5 lysine demethylase family substrate preference and identification of novel substrates

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