Investigator:  Ying Zhang, University of Rhode Island

Mentor:  Rebecca Page, Brown University

Scientific Theme:  Neuroscience & Cancer

Abstract:  The serine/threonine protein phosphatase 1 (PP1) catalyzes the dephosphorylation of hundreds of protein targets, including many key molecules in tumor suppression, neuronal signaling, and the regulation of various cellular processes. Despite their substrate promiscuity, PP1 activity in the cell is rather specific and is tightly regulated by its interaction with hundreds of PP1 regulatory proteins. Thus, one primary challenge in the PP1 research is to understand how their functional specificity is mediated by the binding of diverse regulators. Over the past few years, structural determination of at least eight PP1 holoenzymes has provided significant insights into the interactions between PP1 and PP1 regulators, according to which up to ten binding motifs has been identified. However, the experimentally determination of PP1 holoenzyme structures is challenging. A comprehensive understanding is currently still lacking on the diversity of PP1-binding proteins and the usage of PP1-binding motifs. In the proposed project, we aim to solve this problem by developing a computational procedure for a broader survey of the diversity and distribution of PP1-binding proteins. This computational procedure will take advantage of the knowledge obtained from structural-based studies and extend our understanding into the function of many other PP1 holoenzymes through sequencebased identifications. The proposed study will set the stage for the identification of novel PP1-binding proteins and novel regulatory mechanisms, which will be the focus of future funding applications to the NIH and other agencies.

Human Health Relevance:  The proposed project will facilitate the construction of a preliminary data set and a preliminary protocol for the study of PP1, a functionally essential serine/threonine phosphatase that participates in the regulation of a plethora of pathological processes, including cancer, neurodegenerative diseases, type 2 diabetes, heart failure and viral diseases.