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<p>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, <i>Drosophila melanogaster</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月1日

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  • Jia Liu,
  • Cang Wu,
  • Yuyang Liu,
  • Qiangou Chen,
  • Yuzhen Ding,
  • Zhiqiao Lin,
  • Lifeng Pan,
  • Kang Xiao,
  • Jianchao Li,
  • Zhongmin Liu,
  • Wei Liu

摘要

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.