Both intrinsic substrate preference and network context contribute to substrate selection of classical tyrosine phosphatases

Anita Palma, Michele Tinti, Serena Paoluzi, Elena Santonico, Bernd Willem Brandt, Rob Hooft Van Huijsduijnen, Antonia Masch, Jaap Heringa, Mike Schutkowski, Luisa Castagnoli, Gianni Cesareni

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Reversible tyrosine phosphorylation is a widespread posttranslational modification mechanism underlying cell physiology. Thus, understanding the mechanisms responsible for substrate selection by kinases and phosphatases is central to our ability to model signal transduction at a system level. Classical protein-tyrosine phosphatases can exhibit substrate specificity in vivo by combining intrinsic enzymatic specificity with the network of protein-protein interactions, which positions the enzymes in close proximity to their substrates. Here we use a high throughput approach, based on high density phosphopeptide chips, to determine the in vitro substrate preference of 16 members of the protein-tyrosine phosphatase family. This approach helped identify one residue in the substrate binding pocket of the phosphatase domain that confers specificity for phosphopeptides in a specific sequence context. We also present a Bayesian model that combines intrinsic enzymatic specificity and interaction information in the context of the human protein interaction network to infer new phosphatase substrates at the proteome level.

Original languageEnglish
Pages (from-to)4942-4958
Number of pages17
JournalJournal of Biological Chemistry
Volume292
Issue number12
DOIs
Publication statusPublished - 24 Mar 2017

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Phosphoric Monoester Hydrolases
Tyrosine
Phosphopeptides
Protein Tyrosine Phosphatases
Substrates
Protein Interaction Maps
Cell Physiological Phenomena
Proteome
Post Translational Protein Processing
Substrate Specificity
Signal Transduction
Proteins
Phosphotransferases
Phosphorylation
Signal transduction
Physiology
Enzymes
Throughput

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Palma, A., Tinti, M., Paoluzi, S., Santonico, E., Brandt, B. W., Hooft Van Huijsduijnen, R., ... Cesareni, G. (2017). Both intrinsic substrate preference and network context contribute to substrate selection of classical tyrosine phosphatases. Journal of Biological Chemistry, 292(12), 4942-4958. https://doi.org/10.1074/jbc.M116.757518
Palma, Anita ; Tinti, Michele ; Paoluzi, Serena ; Santonico, Elena ; Brandt, Bernd Willem ; Hooft Van Huijsduijnen, Rob ; Masch, Antonia ; Heringa, Jaap ; Schutkowski, Mike ; Castagnoli, Luisa ; Cesareni, Gianni. / Both intrinsic substrate preference and network context contribute to substrate selection of classical tyrosine phosphatases. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 12. pp. 4942-4958.
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Palma, A, Tinti, M, Paoluzi, S, Santonico, E, Brandt, BW, Hooft Van Huijsduijnen, R, Masch, A, Heringa, J, Schutkowski, M, Castagnoli, L & Cesareni, G 2017, 'Both intrinsic substrate preference and network context contribute to substrate selection of classical tyrosine phosphatases' Journal of Biological Chemistry, vol. 292, no. 12, pp. 4942-4958. https://doi.org/10.1074/jbc.M116.757518

Both intrinsic substrate preference and network context contribute to substrate selection of classical tyrosine phosphatases. / Palma, Anita; Tinti, Michele; Paoluzi, Serena; Santonico, Elena; Brandt, Bernd Willem; Hooft Van Huijsduijnen, Rob; Masch, Antonia; Heringa, Jaap; Schutkowski, Mike; Castagnoli, Luisa; Cesareni, Gianni.

In: Journal of Biological Chemistry, Vol. 292, No. 12, 24.03.2017, p. 4942-4958.

Research output: Contribution to JournalArticleAcademicpeer-review

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