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Substrate recognition principles for the PP2A-B55 protein phosphatase
Open accessPreprint — published as 10.1126/sciadv.adp5491 · Paper page
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 modelling 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 complex by binding to an α-helical recruitment module in RBM7. Collectively, our findings provide a framework for the understanding and interrogation of PP2A-B55 in health and disease. One sentence summary: α-helices in PP2A-B55 substrates bind a conserved pocket on B55 through a common mechanism that is conserved in eukaryotes.
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Metadata
- Authors
- Kruse, T., Garvanska, D. H., Varga, J., Garland, W., McEwan, B., Hein, J. B., Weisser, M. B., Puy, I. B., Chan, C. B., Parrila, P. S., Mendez, B. L., Arulanandam, J., Schueler-Furman, O., Jensen, T. H., Kettenbach, A., & Nilsson, J.
- Affiliations
- Novo Nordisk Foundation (DK)
- Hebrew University of Jerusalem (IL)
- Aarhus University (DK)
- Dartmouth College (US)
- Corresponding author
- Nilsson, Jakob
- ORCID
- Venue
- Science Advances
- Publisher
- openRxiv
- Published
- 2024-02-11
- Volume
- 10
- Issue
- 40
- Pages
- eadp5491-eadp5491
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11446282
- OpenAlex
- W4403052425
- Cited by
- 26
- References
- 2
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 1
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- European Commission (860517)
- Novo Nordisk
- Novo Nordisk Fonden (NNF20OC0065098, NNF23OC0082227)
- National Cancer Institute (P30CA023108)
- National Institute of General Medical Sciences (R35GM119455)
- HORIZON EUROPE European Research Council (101054950)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- PP2A-B55, protein phosphatase, substrate recognition, substrate binding, alpha-helix, mutation scanning, AlphaFold, deep learning protein design, peptide inhibitors, RBM7, protein-protein interaction
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