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PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions

Author

Listed:
  • Sarah Lemaire

    (University of Leuven)

  • Mónica Ferreira

    (University of Leuven)

  • Zander Claes

    (University of Leuven)

  • Rita Derua

    (University of Leuven)

  • Madryn Lake

    (University of Leuven)

  • Gerd Hoeven

    (University of Leuven)

  • Fabienne Withof

    (University of Leuven)

  • Xinyu Cao

    (University of Leuven)

  • Elora C. Greiner

    (Geisel School of Medicine at Dartmouth
    Dartmouth Cancer Center)

  • Arminja N. Kettenbach

    (Geisel School of Medicine at Dartmouth
    Dartmouth Cancer Center)

  • Aleyde Eynde

    (University of Leuven)

  • Mathieu Bollen

    (University of Leuven)

Abstract

Protein Ser/Thr phosphatase PP1 is always associated with one or two regulatory subunits or RIPPOs. One of the earliest evolved RIPPOs is PPP1R2, also known as Inhibitor-2. Since its discovery nearly 5 decades ago, PPP1R2 has been variously described as an inhibitor, activator or (metal) chaperone of PP1, but it is still unknown how PPP1R2 affects the function of PP1 in intact cells. Here, using specific research tools, we demonstrate that PPP1R2 stabilises a subgroup of PP1 holoenzymes, exemplified by PP1:RepoMan, thereby promoting the dephosphorylation of their substrates. Mechanistically, the recruitment of PPP1R2 disrupts an inhibitory, fuzzy interaction between the C-terminal tail and catalytic domain of PP1, and generates an additional C-terminal RepoMan-interaction site. The resulting holoenzyme is further stabilized by a direct PPP1R2:RepoMan interaction, which renders it refractory to competitive disruption by RIPPOs that do not interact with PPP1R2. Our data demonstrate that PPP1R2 modulates the function of PP1 by altering the balance between holoenzymes through stabilisation of specific subunit interactions.

Suggested Citation

  • Sarah Lemaire & Mónica Ferreira & Zander Claes & Rita Derua & Madryn Lake & Gerd Hoeven & Fabienne Withof & Xinyu Cao & Elora C. Greiner & Arminja N. Kettenbach & Aleyde Eynde & Mathieu Bollen, 2024. "PPP1R2 stimulates protein phosphatase-1 through stabilisation of dynamic subunit interactions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54256-4
    DOI: 10.1038/s41467-024-54256-4
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    References listed on IDEAS

    as
    1. Xinyu Cao & Madryn Lake & Gerd Hoeven & Zander Claes & Javier del Pino García & Sarah Lemaire & Elora C. Greiner & Spyridoula Karamanou & Aleyde Eynde & Arminja N. Kettenbach & Daniel Natera de Benito, 2024. "SDS22 coordinates the assembly of holoenzymes from nascent protein phosphatase-1," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. M. Teresa Bertran & Stéphane Mouilleron & Yanxiang Zhou & Rakhi Bajaj & Federico Uliana & Ganesan Senthil Kumar & Audrey Drogen & Rebecca Lee & Jennifer J. Banerjee & Simon Hauri & Nicola O’Reilly & M, 2019. "ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    3. Mohammed Terrak & Frederic Kerff & Knut Langsetmo & Terence Tao & Roberto Dominguez, 2004. "Structural basis of protein phosphatase 1 regulation," Nature, Nature, vol. 429(6993), pages 780-784, June.
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