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<p>Serine/threonine phosphoprotein phosphatases (PPPs) are conserved metalloenzymes and key regulators of intracellular signaling. Here, we systematically map the components and residues required for PP2A-like phosphatase (PP2A/PP4/PP6) function using genome-wide CRISPR knockout and focused base editing screens and provide this as a comprehensive resource. We uncover the reductase CYB5R4 as an evolutionarily conserved activator of PP4 and PP6, but not PP2A. We demonstrate that PP4 and PP6 are redox sensitive and require CYB5R4 to reduce the active site metal ions for activation. Mechanistically, this involves the selective binding of PP4 and PP6 through binding elements in the N-terminal tail of CYB5R4 and CYB5R4-bound heme serving as an electron donor for the active site. We further show that this activation is critical for regulating the response to DNA damage. Our work hints that active site metal ion redox regulation mediates crosstalk between the oxidative state of the cell and specific phosphatase activities.</p>

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A functional map of phosphoprotein phosphatase regulation identifies an evolutionarily conserved reductase for the catalytic metal ions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Bob Meeusen,
  • Sara M. Ambjørn,
  • Jiri Veis,
  • Rachel C. Riley,
  • Gianmatteo Vit,
  • Brooke L. Brauer,
  • Mads H. Møller,
  • Elora C. Greiner,
  • Camilla B. Chan,
  • Anna M. Schmoker,
  • Blanca Lopez Mendez,
  • Melanie B. Weisser,
  • Dimitriya H. Garvanska,
  • Hao Zhu,
  • Norman E. Davey,
  • Arminja N. Kettenbach,
  • Egon Ogris,
  • Jakob Nilsson

摘要

Serine/threonine phosphoprotein phosphatases (PPPs) are conserved metalloenzymes and key regulators of intracellular signaling. Here, we systematically map the components and residues required for PP2A-like phosphatase (PP2A/PP4/PP6) function using genome-wide CRISPR knockout and focused base editing screens and provide this as a comprehensive resource. We uncover the reductase CYB5R4 as an evolutionarily conserved activator of PP4 and PP6, but not PP2A. We demonstrate that PP4 and PP6 are redox sensitive and require CYB5R4 to reduce the active site metal ions for activation. Mechanistically, this involves the selective binding of PP4 and PP6 through binding elements in the N-terminal tail of CYB5R4 and CYB5R4-bound heme serving as an electron donor for the active site. We further show that this activation is critical for regulating the response to DNA damage. Our work hints that active site metal ion redox regulation mediates crosstalk between the oxidative state of the cell and specific phosphatase activities.