Substrate recognition principles for the PP2A-B55 protein phosphatase.

التفاصيل البيبلوغرافية
العنوان: Substrate recognition principles for the PP2A-B55 protein phosphatase.
المؤلفون: Kruse T; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Garvanska DH; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Varga J; Department of Microbiology and Molecular Genetics, Institute for Biomedical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 9112001, Israel., Garland W; Department of Molecular Biology and Genetics, Universitetsbyen 81, Aarhus University, Aarhus, Denmark., McEwan B; Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA., Hein JB; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark.; Current address: Amgen Research Copenhagen, Rønnegade 8, 5, 2100 Copenhagen, Denmark., Weisser MB; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Puy IB; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Chan CB; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Parrila PS; Gene Center Munich, Ludwig-Maximilians- Universität München, Munich, 81377, Germany., Mendez BL; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Arulanandam J; Gene Center Munich, Ludwig-Maximilians- Universität München, Munich, 81377, Germany.; Wellcome Centre for Cell Biology, University of Edinburg, Edinburgh, EH9 3BF, UK., Schueler-Furman O; Department of Microbiology and Molecular Genetics, Institute for Biomedical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 9112001, Israel., Jensen TH; Department of Molecular Biology and Genetics, Universitetsbyen 81, Aarhus University, Aarhus, Denmark., Kettenbach A; Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA., Nilsson J; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 13. Date of Electronic Publication: 2024 Feb 13.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: 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.
Competing Interests: Conflict of interest The authors have no conflict of interest.
معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; R35 GM119455 United States GM NIGMS NIH HHS
تواريخ الأحداث: Date Created: 20240219 Latest Revision: 20240226
رمز التحديث: 20240226
مُعرف محوري في PubMed: PMC10871369
DOI: 10.1101/2024.02.10.579793
PMID: 38370611
قاعدة البيانات: MEDLINE
الوصف
DOI:10.1101/2024.02.10.579793