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Project

Life-course regulators of protein phosphatase-1

Protein phosphatase-1 (PP1) catalyzes a substantial fraction of all protein Ser/Thr-dephosphorylation events and is essential for eukaryotic life. It forms highly selective and tightly regulated holoenzymes through association with a vast array of regulatory polypeptides. The large majority of PP1 interactors function as subcellular targeting subunits or substrate recruiters. A notable exception are the three first evolved and most conserved PP1 interactors, known as Inhibitor-2 (I2), Inhibitor-3 (I3) and SDS22, which have been described as both inhibitors and activators of PP1. Based upon the existing literature and a substantial set of preliminary data, we hypothesize that these ‘ancient’ regulators serve seemingly contradictory functions because they contribute to both the biogenesis and degradation of PP1. Using newly designed degron- and knockin-cell lines, we will delineate the role of I2, I3 and SDS22 in the biogenesis of PP1, with a special focus on the stabilization of nascent PP1, holoenzyme assembly and metal incorporation. We will also explore the contribution of SDS22 and I3 to a putative quality-control mechanism that removes dysfunctional PP1. Finally, we will examine how SDS22 and I2 function in cell-cycle regulation of PP1 through metal (un)loading. This project will generate key molecular insights into the life-course regulation of PP1 that are of interest for the further development of PP1 as a therapeutic target.

Date:1 Jan 2021 →  Today
Keywords:protein phosphatase-1, therapeutic target
Disciplines:Cell signalling