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

Jia Liu, Cang Wu, Yuyang Liu, Qiangou Chen, Yuzhen Ding, Zhiqiao Lin, Lifeng Pan, Kang Xiao, Jianchao Li (), Zhongmin Liu () and Wei Liu ()
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Jia Liu: Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center
Cang Wu: 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
Jianchao Li: South China University of Technology
Zhongmin Liu: Southern University of Science and Technology
Wei Liu: Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58261-z

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