Structural insights into the dual Ca2+-sensor-mediated activation of the PPEF phosphatase family
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 Ca<sup>2+</sup>-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 Ca<sup>2+</sup>, 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup>-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.
Authors
- Zhiqiao Lin
- Qiangou Chen
- Yuzhen Ding
- Kang Xiao (ORCID: https://orcid.org/0000-0002-7666-2460)
- Lifeng Pan (ORCID: https://orcid.org/0000-0002-9229-6288)
- Cang Wu (ORCID: https://orcid.org/0000-0002-6218-8569)
- Zhongmin Liu (ORCID: https://orcid.org/0000-0002-3280-3890)
- Jianchao Li (ORCID: https://orcid.org/0000-0002-8921-1626)
- Yuyang Liu (ORCID: https://orcid.org/0000-0001-5632-7764)
- Jia Liu (ORCID: https://orcid.org/0000-0002-8262-4997)
- Wei Liu (ORCID: https://orcid.org/0000-0001-8250-2562)
Institutions
- Chinese Academy of Sciences (CN)
- Southern University of Science and Technology (CN)
- HKUST Shenzhen Research Institute (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Peking University Shenzhen Hospital (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- University of Hong Kong (HK)
- South China University of Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s41467-025-58261-z
- Primary Topic
- ATP Synthase and ATPases Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Tsinghua University
- Hong Kong University of Science and Technology
- University of Science and Technology of China
- Hanshan Normal University
- Southern University of Science and Technology
- Basic and Applied Basic Research Foundation of Guangdong Province