TY - JOUR
T1 - Substrate recognition principles for the PP2A-B55 protein phosphatase
AU - Kruse, Thomas
AU - Garvanska, Dimitriya H.
AU - Varga, Julia K.
AU - Garland, William
AU - McEwan, Brennan C.
AU - Hein, Jamin B.
AU - Weisser, Melanie Bianca
AU - Benavides-Puy, Iker
AU - Chan, Camilla Bachman
AU - Sotelo-Parrilla, Paula
AU - Lopez Mendez, Blanca
AU - Jeyaprakash, A. Arockia
AU - Schueler-Furman, Ora
AU - Jensen, Torben Heick
AU - Kettenbach, Arminja N.
AU - Nilsson, Jakob
N1 - Publisher Copyright:
Copyright © 2024 The Authors, some rights reserved.
PY - 2024/10/4
Y1 - 2024/10/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85205528683
U2 - 10.1126/sciadv.adp5491
DO - 10.1126/sciadv.adp5491
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C2 - 39356758
AN - SCOPUS:85205528683
SN - 2375-2548
VL - 10
JO - Science advances
JF - Science advances
IS - 40
M1 - eadp5491
ER -