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Sci Adv. 2018 Nov 28;4(11):eaav2623. doi: 10.1126/sciadv.aav2623. eCollection 2018 Nov.

A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity.

Author information

1
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
2
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3
Department of Microbiology, Immunology, and Biochemistry, Wayne State University School of Medicine, Detroit, MI 48201, USA.
4
Department of Translational Science and Molecular Medicine and Integrated Mass Spectrometry Unit, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA.
5
EpiCypher Inc., Research Triangle Park, NC 27709, USA.
6
Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439, USA.

Abstract

Lysine methylation is a key regulator of histone protein function. Beyond histones, few connections have been made to the enzymes responsible for the deposition of these posttranslational modifications. Here, we debut a high-throughput functional proteomics platform that maps the sequence determinants of lysine methyltransferase (KMT) substrate selectivity without a priori knowledge of a substrate or target proteome. We demonstrate the predictive power of this approach for identifying KMT substrates, generating scaffolds for inhibitor design, and predicting the impact of missense mutations on lysine methylation signaling. By comparing KMT selectivity profiles to available lysine methylome datasets, we reveal a disconnect between preferred KMT substrates and the ability to detect these motifs using standard mass spectrometry pipelines. Collectively, our studies validate the use of this platform for guiding the study of lysine methylation signaling and suggest that substantial gaps exist in proteome-wide curation of lysine methylomes.

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