A strategy to disentangle direct and indirect effects on (de)phosphorylation by chemical modulators of the phosphatase PP1 in complex cellular contexts

Hoermann, Bernhard; Dürr, Eva-Maria; Ludwig, Christina; Ercan, Melda; Köhn, Maja

doi:10.1039/d3sc04746f

Chem. Sci.

2024

DOI: 10.1039/d3sc04746f

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A strategy to disentangle direct and indirect effects on (de)phosphorylation by chemical modulators of the phosphatase PP1 in complex cellular contexts

Bernhard Hoermann,

Eva-Maria Dürr,

Christina Ludwig

et al.

Abstract: Chemical activators and inhibitors are useful probes to identify substrates and downstream effects of enzymes; however, due to the complex signaling environment within cells, it is challenging to distinguish between...

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Photo‐Claisen Rearrangement in a Coumarin‐Caged Peptide Leads to a Surprising Enzyme Hyperactivation

Maller,

Marouda,

Köhn

2024

ChemBioChem

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Protein phosphatase‐1 (PP1) is a ubiquitous enzyme counteracting hundreds of kinases in cells. PP1 interacts with regulatory proteins via an RVxF peptide motif that binds to a hydrophobic groove on the enzyme. PP1‐disrupting peptides (PDPs) compete with these regulatory proteins, leading to the release of the active PP1 subunit and promoting substrate dephosphorylation. Building on previous strategies employing the ortho‐nitrobenzyl (o‐Nb) group, we introduced coumarin derivatives into a PDP via an ether bond to explore their effects on PP1 activity. Surprisingly, our study revealed that the coumarin‐caged peptides (PDP‐DEACM and PDP‐CM) underwent a photo‐Claisen rearrangement, resulting in an unexpected hyperactivation of PP1. Our findings underscore the importance of linker design in controlling uncaging efficiency and highlight the need for comprehensive in vitro analysis before cellular experiments.

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Photo‐Claisen Rearrangement in a Coumarin‐Caged Peptide Leads to a Surprising Enzyme Hyperactivation

Maller,

Marouda,

Köhn

2024

ChemBioChem

View full text Add to dashboard Cite

show abstract

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A strategy to disentangle direct and indirect effects on (de)phosphorylation by chemical modulators of the phosphatase PP1 in complex cellular contexts

Abstract: Chemical activators and inhibitors are useful probes to identify substrates and downstream effects of enzymes; however, due to the complex signaling environment within cells, it is challenging to distinguish between...

Cited by 1 publication

References 58 publications

Photo‐Claisen Rearrangement in a Coumarin‐Caged Peptide Leads to a Surprising Enzyme Hyperactivation

Photo‐Claisen Rearrangement in a Coumarin‐Caged Peptide Leads to a Surprising Enzyme Hyperactivation

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