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

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. Functional genome-wide knockout and focused base editing screens uncover CYB5R4 as an evolutionarily conserved reductase for the active site metal ions of the PP4 and PP6 phosphoprotein phosphatases.

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Journal
Nature Communications
Published
2026-06-18
DOI
https://doi.org/10.1038/s41467-026-74262-y
Primary Topic
Cell death mechanisms and regulation
Type
article
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article

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

Egon Ogris, Bob Meeusen, Blanca López‐Méndez, Jakob Nilsson et al.
Nature Communications
Cell death mechanisms and regulation
article

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

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

Abstract

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. Functional genome-wide knockout and focused base editing screens uncover CYB5R4 as an evolutionarily conserved reductase for the active site metal ions of the PP4 and PP6 phosphoprotein phosphatases.

Nature Communications
Dartmouth College (US), St. Jude Children's Research Hospital (US), Institute of Cancer Research (GB), Novo Nordisk Foundation (DK), Max Perutz Labs (AT), Dartmouth Psychiatric Research Center (US), University of Kansas Medical Center (US), Danish Cancer Society (DK), Dartmouth Cancer Center, Medical University of Vienna (AT)
Openalex Percentile: Top 10%
Cell death mechanisms and regulation
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