Substrate recognition principles for the PP2A-B55 protein phosphatase

The PP2A-B55 phosphatase regulates a plethora of signaling pathways throughout eukaryotes. How PP2A-B55 selects its substrates presents a severe knowledge gap. By integrating AlphaFold modeling with comprehensive high-resolution mutational scanning, we show that α helices in substrates bind B55 through an evolutionary conserved mechanism. Despite a large diversity in sequence and composition, these α helices share key amino acid determinants that engage discrete hydrophobic and electrostatic patches. Using deep learning protein design, we generate a specific and potent competitive peptide inhibitor of PP2A-B55 substrate interactions. With this inhibitor, we uncover that PP2A-B55 regulates the nuclear exosome targeting (NEXT) complex by binding to an α-helical recruitment module in the RNA binding protein 7 (RBM7), a component of the NEXT complex. Collectively, our findings provide a framework for the understanding and interrogation of PP2A-B55 function in health and disease.

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Publication Details

Journal
Science Advances
Published
2024-10-02
DOI
https://doi.org/10.1126/sciadv.adp5491
Citations
22
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
5.14

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article

Substrate recognition principles for the PP2A-B55 protein phosphatase

Blanca López‐Méndez, Jamin B. Hein, Dimitriya H. Garvanska, Jakob Nilsson et al.
22 citations
Science Advances
RNA Research and Splicing
5.14
article

Substrate recognition principles for the PP2A-B55 protein phosphatase

Blanca López‐Méndez, Jamin B. Hein, Dimitriya H. Garvanska, Jakob Nilsson, Julia K. Varga, Ora Schueler‐Furman, Paula Sotelo‐Parrilla, Thomas Kruse, William A. Garland, Melanie Weisser, Brennan C McEwan, Arminja N. Kettenbach, Torben Heick Jensen, Iker Benavides-Puy, A. Arockia Jeyaprakash, Camilla Bachman Chan
article en
22 citations

Abstract

The PP2A-B55 phosphatase regulates a plethora of signaling pathways throughout eukaryotes. How PP2A-B55 selects its substrates presents a severe knowledge gap. By integrating AlphaFold modeling with comprehensive high-resolution mutational scanning, we show that α helices in substrates bind B55 through an evolutionary conserved mechanism. Despite a large diversity in sequence and composition, these α helices share key amino acid determinants that engage discrete hydrophobic and electrostatic patches. Using deep learning protein design, we generate a specific and potent competitive peptide inhibitor of PP2A-B55 substrate interactions. With this inhibitor, we uncover that PP2A-B55 regulates the nuclear exosome targeting (NEXT) complex by binding to an α-helical recruitment module in the RNA binding protein 7 (RBM7), a component of the NEXT complex. Collectively, our findings provide a framework for the understanding and interrogation of PP2A-B55 function in health and disease.

Science AdvancesVol. 10(40)
Dartmouth College (US), Hebrew University of Jerusalem (IL), Aarhus University (DK), Novo Nordisk Foundation (DK), Aarhus University Hospital (DK), Wellcome Centre for Cell Biology (GB), Ludwig-Maximilians-Universität München (DE)
European Commission, Novo Nordisk
Openalex Percentile: Top 4%
RNA Research and Splicing
5.14
DOIOpen Access PDFOpenAlex
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