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PP1TOOLS Report Summary

Project ID: 336567
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - PP1TOOLS (Development of chemical biology tools for the elucidation of protein phosphatase-1 substrates and druggability)

Within intracellular signaling networks, protein phosphatases, which remove phosphate groups from amino acids such as serine (Ser) and threonine (Thr) are counter players of protein kinases and play crucial roles in health and disease. Protein serine/threonine-specific phosphatases (PSTPs) are considered as not useful drug targets 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 a majority of Ser and Thr dephosphorylations in eukaryotic cells, counteracting more than hundred 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), and HIV (viral translation). Currently, there are few chemical modulators available that target PP1 selectively. We developed the PP1-disrupting peptides (PDPs) that selectively activate PP1 in intact cells, leading to rapid dephosphorylation of nearby PP1 substrates. The activator does not act on the most closely related protein phosphatase-2A, nor on the family member PP2B.

This project aims to generate and apply tools for the investigation of PP1, in part based on our previously developed activator. The tools include selective, photo-releasable chemical inhibitors and activators, semisynthetic proteins and non-hydrolyzable phosphoSer-analogs, and they will be applied to study PP1–substrate interactions and help identify the correlating interacting proteins. Current progress includes a medicinal chemistry-based optimization of microcystin, which is a natural toxin that indiscriminately targets PP1 and PP2A, through which we have discovered a selective PP2A inhibitor and learned about determinants for targeting the phosphatase selectively.

The proposed research will provide 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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