Dissecting the sequence determinants for dephosphorylation by the catalytic subunits of phosphatases PP1 and PP2A

Bernhard Hoermann, Thomas Kokot, Dominic Helm, Stephanie Heinzlmeir, Jeremy E. Chojnacki, Thomas Schubert, Christina Ludwig, Anna Berteotti, Nils Kurzawa, Bernhard Kuster, Mikhail M. Savitski and Maja Köhn ()
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Bernhard Hoermann: Faculty of Biology, Institute of Biology III, University of Freiburg
Thomas Kokot: Faculty of Biology, Institute of Biology III, University of Freiburg
Dominic Helm: European Molecular Biology Laboratory, Proteomics Core Facility
Stephanie Heinzlmeir: Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM)
Jeremy E. Chojnacki: Faculty of Biology, Institute of Biology III, University of Freiburg
Thomas Schubert: Signalling Research Centres BIOSS and CIBSS, University of Freiburg
Christina Ludwig: Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich (TUM)
Anna Berteotti: European Molecular Biology Laboratory, Genome Biology Unit
Nils Kurzawa: European Molecular Biology Laboratory, Genome Biology Unit
Bernhard Kuster: Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM)
Mikhail M. Savitski: European Molecular Biology Laboratory, Genome Biology Unit
Maja Köhn: Faculty of Biology, Institute of Biology III, University of Freiburg

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract The phosphatases PP1 and PP2A are responsible for the majority of dephosphorylation reactions on phosphoserine (pSer) and phosphothreonine (pThr), and are involved in virtually all cellular processes and numerous diseases. The catalytic subunits exist in cells in form of holoenzymes, which impart substrate specificity. The contribution of the catalytic subunits to the recognition of substrates is unclear. By developing a phosphopeptide library approach and a phosphoproteomic assay, we demonstrate that the specificity of PP1 and PP2A holoenzymes towards pThr and of PP1 for basic motifs adjacent to the phosphorylation site are due to intrinsic properties of the catalytic subunits. Thus, we dissect this amino acid specificity of the catalytic subunits from the contribution of regulatory proteins. Furthermore, our approach enables discovering a role for PP1 as regulator of the GRB-associated-binding protein 2 (GAB2)/14-3-3 complex. Beyond this, we expect that this approach is broadly applicable to detect enzyme-substrate recognition preferences.

Date: 2020
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DOI: 10.1038/s41467-020-17334-x

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