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Development of chemical biology tools for the elucidation of protein phosphatase-1 substrates and druggability

Development of chemical biology tools for the elucidation of protein phosphatase-1 substrates and druggability

Objective

Protein serine/threonine phosphatases (PSTPs) are considered undruggable although they are involved in the most prominent post-translational modifications. This is mainly due to an apparent lack of substrate specificity. One important PSTP is protein phosphatase-1 (PP1), a ubiquitous PSTP that is predicted to catalyze about 1/3rd of Ser and Thr dephosphorylations in eukaryotic cells, counteracting hundreds of kinases. PP1 has broad substrate specificity but is restrained in vivo by numerous PP1-interacting proteins functioning for example as substrate-targeting proteins and forming specific holoenzymes with PP1. PP1 holoenzymes play a role in many different diseases such as cancer (counteracting oncogenic kinases), diabetes (insulin release), Alzheimer’s (dephosphorylation of Tau protein) and HIV (viral translation). Currently, there are no chemical modulators available that target PP1 selectively, except that we recently developed the first compound that selectively activates PP1 in intact cells, leading to rapid dephosphorylation of PP1 substrates. The activator does not act on the most closely related protein phosphatase-2A. This proposal aims to generate and apply tools for the investigation of PP1, in part based on our previously developed activator. The tools include selective, photo- and enzymatically releasable chemical inhibitors and activators and semisynthetic proteins, and they will be applied to study PP1–substrate interactions and help identify the correlating interacting proteins. The proposed research will provide long-sought selective chemical tools to study PP1 by applying new concepts of activator and inhibitor design using peptide and small molecule chemistry to an enzyme class that is difficult to be targeted chemically. This research program will contribute to a much more detailed understanding of PP1 biology, and will open doors to investigate PP1 and its holoenzymes as drug targets.
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Principal Investigator

Maja Banks-Köhn (Prof.)

Host institution

ALBERT-LUDWIGS-UNIVERSITAET FREIBURG

Address

Fahnenbergplatz
79098 Freiburg

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 488 332,76

Principal Investigator

Maja Banks-Köhn (Prof.)

Administrative Contact

Christian Jäger (Mr.)

Beneficiaries (2)

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ALBERT-LUDWIGS-UNIVERSITAET FREIBURG

Germany

EU Contribution

€ 488 332,76

EUROPEAN MOLECULAR BIOLOGY LABORATORY

Germany

EU Contribution

€ 676 183,24

Project information

Grant agreement ID: 336567

Status

Closed project

  • Start date

    1 January 2014

  • End date

    31 December 2018

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 164 516

  • EU contribution

    € 1 164 516

Hosted by:

ALBERT-LUDWIGS-UNIVERSITAET FREIBURG

Germany