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Substrate recognition principles for the PP2A-B55 protein phosphatase.
Kruse, Thomas; Garvanska, Dimitriya H; Varga, Julia K; Garland, William; McEwan, Brennan C; Hein, Jamin B; Weisser, Melanie Bianca; Benavides-Puy, Iker; Chan, Camilla Bachman; Sotelo-Parrilla, Paula; Mendez, Blanca Lopez; Jeyaprakash, A Arockia; Schueler-Furman, Ora; Jensen, Torben Heick; Kettenbach, Arminja N; Nilsson, Jakob.
Afiliação
  • 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 JK; 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, Aarhus University, Universitetsbyen 81, Aarhus, Denmark.
  • McEwan BC; 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.
  • Weisser MB; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
  • Benavides-Puy I; 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.
  • Sotelo-Parrilla P; 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.
  • Jeyaprakash AA; Gene Center Munich, Ludwig-Maximilians-Universität München, Munich 81377, Germany.
  • Schueler-Furman O; Wellcome Centre for Cell Biology, University of Edinburg, Edinburgh EH9 3BF, UK.
  • Jensen TH; Department of Microbiology and Molecular Genetics, Institute for Biomedical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
  • Kettenbach AN; Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, Aarhus, Denmark.
  • Nilsson J; Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.
Sci Adv ; 10(40): eadp5491, 2024 Oct 04.
Article em En | MEDLINE | ID: mdl-39356758
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ligação Proteica / Proteína Fosfatase 2 Limite: Humans Idioma: En Revista: Sci Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Dinamarca País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ligação Proteica / Proteína Fosfatase 2 Limite: Humans Idioma: En Revista: Sci Adv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Dinamarca País de publicação: Estados Unidos