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A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis

Author

Listed:
  • Pierre Raia

    (University of Geneva)

  • Kitaik Lee

    (University of Geneva
    National Cancer Institute (NCI))

  • Simon M. Bartsch

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie
    Humboldt-Universität zu Berlin)

  • Felix Rico-Resendiz

    (University of Geneva)

  • Daniela Portugal-Calisto

    (University of Zürich)

  • Oscar Vadas

    (University of Geneva)

  • Vikram Govind Panse

    (University of Zürich
    University of Zürich)

  • Dorothea Fiedler

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie
    Humboldt-Universität zu Berlin)

  • Michael Hothorn

    (University of Geneva)

Abstract

Inositol pyrophosphates (PP-InsPs) are eukaryotic nutrient messengers. The N-terminal kinase domain of diphosphoinositol pentakisphosphate kinase (PPIP5K) generates the messenger 1,5-InsP8, the C-terminal phosphatase domain catalyzes PP-InsP breakdown. The balance between kinase and phosphatase activities regulates 1,5-InsP8 levels. Here, we present crystal structures of the apo and substrate-bound PPIP5K phosphatase domain from S. cerevisiae (ScVip1PD). ScVip1PD is a phytase-like inositol 1-pyrophosphate histidine phosphatase with two conserved catalytic motifs. The enzyme has a strong preference for 1,5-InsP8 and is inhibited by inorganic phosphate. It contains an α-helical insertion domain stabilized by a structural Zn2+ binding site, and a unique GAF domain that channels the substrate to the active site. Mutations that alter the active site, restrict the movement of the GAF domain, or change the substrate channel’s charge inhibit the enzyme activity in vitro, and Arabidopsis VIH2 in planta. Our work reveals the structure, enzymatic mechanism and regulation of eukaryotic PPIP5K phosphatases.

Suggested Citation

  • Pierre Raia & Kitaik Lee & Simon M. Bartsch & Felix Rico-Resendiz & Daniela Portugal-Calisto & Oscar Vadas & Vikram Govind Panse & Dorothea Fiedler & Michael Hothorn, 2025. "A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56937-0
    DOI: 10.1038/s41467-025-56937-0
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    References listed on IDEAS

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