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Project

Chaperone-guided biogenesis and activity regulation of protein phosphatase-1.

The synthesis of enzymes involves multiple, tightly regulated steps including transcription, translation, post-translational maturation, and the association of co-factors and regulatory subunits. Protein phosphatase-1 (PP1) is a very conserved and essential eukaryotic Ser/Thr phosphatase that functions as the catalytic subunit of at least 200 distinct holoenzymes. However, it is not understood how PP1 acquires its native conformation and catalytic-site metals. Neither is it known how PP1 forms holoenzymes through association with regulatory subunits that determine when and where the phosphatase acts. Here, we propose to explore the role of two ancient PP1-interacting proteins, i.e. Sds22 and Inhibitor-2, as chaperones that guide the biogenesis of PP1. We will determine the crystal structure of the PP1-Sds22 complex and generate antibodies that are specific for the Sds22-induced conformation of PP1. Also, specifically engineered HeLa cell lines will be generated to study the role of Sds22 and Inhibitor-2 in the biogenesis and activity regulation of PP1. Additional regulators of PP1 biogenesis will be identified in traps of immature forms of PP1 and by a novel technique that enables the tagging of proteins that interact with PP1-Sds22 or PP1-Inhibitor-2. In addition, we will use rabbit reticulocyte lysates to study the biogenesis of PP1 in vitro. Collectively, these experiments are expected to generate key insights into the biogenesis and activity regulation of PP1.

Date:1 Jan 2015 →  31 Dec 2018
Keywords:Chaperone-gemedieerde biogenese
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences