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Molecular basis for the regulation of human phosphorylase kinase by phosphorylation and Ca2+

Author

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  • Ruifang Ma

    (Southern University of Science and Technology)

  • Bowen Du

    (Southern University of Science and Technology)

  • Chen Shi

    (Zhejiang University
    Zhejiang University)

  • Lei Wang

    (Southern University of Science and Technology)

  • Fuxing Zeng

    (Southern University of Science and Technology
    Southern University of Science and Technology)

  • Jie Han

    (Southern University of Science and Technology)

  • Huiyi Guan

    (Southern University of Science and Technology)

  • Yong Wang

    (Zhejiang University
    International Campus of Zhejiang University)

  • Kaige Yan

    (Southern University of Science and Technology
    Southern University of Science and Technology)

Abstract

Phosphorylase kinase (PhK) regulates the degradation of glycogen by integrating diverse signals, providing energy to the organism. Dysfunctional mutations may directly lead to Glycogen Storage Disease type IX (GSD IX), whereas the abnormal expression of PhK is also associated with tumors. Here, we use cryo-electron microscopy (cryo-EM) to resolve its near-atomic structures in the inactive and active states. These structures reveal the interactions and relative locations of the four subunits (αβγδ) within the PhK complex. Phosphorylated α and β subunits induce PhK to present a more compact state, while Ca2+ causes sliding of the δ subunit along the helix of the γ subunit. Both actions synergistically activate PhK by enabling the de-inhibition of the γ subunit. We also identified different binding modes between PhK and its substrate, glycogen phosphorylase (GP), in two distinct states, using cross-linking mass spectrometry (XL-MS). This study provides valuable insights into the regulatory mechanisms of PhK, thereby enhancing our understanding of GSD IX and its implications in tumorigenesis.

Suggested Citation

  • Ruifang Ma & Bowen Du & Chen Shi & Lei Wang & Fuxing Zeng & Jie Han & Huiyi Guan & Yong Wang & Kaige Yan, 2025. "Molecular basis for the regulation of human phosphorylase kinase by phosphorylation and Ca2+," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58363-8
    DOI: 10.1038/s41467-025-58363-8
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