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

Evan M. Cornett, Bradley M. Dickson, Krzysztof Krajewski, Nicholas Spellmon, Andrew Umstead, Robert M. Vaughan, Kevin M. Shaw, Philip P. Versluis, Martis W. Cowles, Joseph S Brunzelle, Zhe Yang, Irving E. Vega, Zu Wen Sun, Scott B. Rothbart*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbereaav2623
JournalScience Advances
Volume4
Issue number11
DOIs
StatePublished - Nov 28 2018

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Methyltransferases
Proteomics
Lysine
Methylation
Proteome
Histones
Missense Mutation
Post Translational Protein Processing
Mass Spectrometry
Enzymes
Proteins

ASJC Scopus subject areas

  • General

Cite this

Cornett, E. M., Dickson, B. M., Krajewski, K., Spellmon, N., Umstead, A., Vaughan, R. M., ... Rothbart, S. B. (2018). A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity. Science Advances, 4(11), [eaav2623]. https://doi.org/10.1126/sciadv.aav2623
Cornett, Evan M. ; Dickson, Bradley M. ; Krajewski, Krzysztof ; Spellmon, Nicholas ; Umstead, Andrew ; Vaughan, Robert M. ; Shaw, Kevin M. ; Versluis, Philip P. ; Cowles, Martis W. ; Brunzelle, Joseph S ; Yang, Zhe ; Vega, Irving E. ; Sun, Zu Wen ; Rothbart, Scott B. / A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity. In: Science Advances. 2018 ; Vol. 4, No. 11.
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Cornett, EM, Dickson, BM, Krajewski, K, Spellmon, N, Umstead, A, Vaughan, RM, Shaw, KM, Versluis, PP, Cowles, MW, Brunzelle, JS, Yang, Z, Vega, IE, Sun, ZW & Rothbart, SB 2018, 'A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity', Science Advances, vol. 4, no. 11, eaav2623. https://doi.org/10.1126/sciadv.aav2623

A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity. / Cornett, Evan M.; Dickson, Bradley M.; Krajewski, Krzysztof; Spellmon, Nicholas; Umstead, Andrew; Vaughan, Robert M.; Shaw, Kevin M.; Versluis, Philip P.; Cowles, Martis W.; Brunzelle, Joseph S; Yang, Zhe; Vega, Irving E.; Sun, Zu Wen; Rothbart, Scott B.

In: Science Advances, Vol. 4, No. 11, eaav2623, 28.11.2018.

Research output: Contribution to journalArticle

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AU - Cornett, Evan M.

AU - Dickson, Bradley M.

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AU - Spellmon, Nicholas

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AU - Vaughan, Robert M.

AU - Shaw, Kevin M.

AU - Versluis, Philip P.

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AU - Sun, Zu Wen

AU - Rothbart, Scott B.

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