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Structural insights into the dual Ca2+-sensor-mediated activation of the PPEF phosphatase family

Author

Listed:
  • Jia Liu

    (Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center)

  • Cang Wu

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

  • Yuyang Liu

    (Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center)

  • Qiangou Chen

    (Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center)

  • Yuzhen Ding

    (Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center)

  • Zhiqiao Lin

    (Chinese Academy of Sciences)

  • Lifeng Pan

    (Chinese Academy of Sciences)

  • Kang Xiao

    (Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center
    Futian)

  • Jianchao Li

    (South China University of Technology)

  • Zhongmin Liu

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

  • Wei Liu

    (Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center
    Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center)

Abstract

Serine/threonine-protein phosphatases with EF-hands (PPEFs) are a family of highly conserved proteins implicated in cancer and neuronal degeneration. The initially characterized member, Drosophila melanogaster retinal degeneration C (RDGC) contains a calmodulin (CaM)-interacting extended-IQ motif and a Ca2+-binding EF-like/EF-hand tandem. However, the molecular regulation of PPEF is poorly understood. In this study, we use cryogenic-electron microscopy to delineate the structures of the RDGC/CaM holoenzyme. In the absence of Ca2+, CaM and the EF-like/EF-hand tandem allow the extended-IQ motif to block substrate access to the catalytic sites, constituting an auto-inhibitory mechanism. Upon Ca2+ binding, CaM and the EF-like/EF-hand tandem drive drastic conformational changes in the extended-IQ motif to unlock the catalytic sites. This dual Ca2+-sensor-mediated activation is evolutionarily conserved in mammals. This study provides mechanistic insight into the molecular activation of PPEFs, paving the way for the development of therapeutic strategies for PPEF-related human diseases.

Suggested Citation

  • Jia Liu & Cang Wu & Yuyang Liu & Qiangou Chen & Yuzhen Ding & Zhiqiao Lin & Lifeng Pan & Kang Xiao & Jianchao Li & Zhongmin Liu & Wei Liu, 2025. "Structural insights into the dual Ca2+-sensor-mediated activation of the PPEF phosphatase family," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58261-z
    DOI: 10.1038/s41467-025-58261-z
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