Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

Abstract

Protein phosphatase 1 (PP1) catalyzes more than half of all phosphoserine/threonine dephosphorylation reactions in mammalian cells. In vivo PP1 does not exist as a free catalytic subunit but is always associated with at least one regulatory PP1-interacting protein (PIP) to generate a large set of distinct holoenzymes. Each PP1 complex controls the dephosphorylation of only a small subset of PP1 substrates. We screened the literature for genetically engineered mouse models and identified models for all PP1 isoforms and 104 PIPs. PP1 itself and at least 49 PIPs were connected to human disease-associated phenotypes. Additionally, phenotypes related to 17 PIPs were clearly linked to altered PP1 function, while such information was lacking for 32 other PIPs. We propose structural reverse genetics, which combines structural characterization of proteins with mouse genetics, to identify new PP1-related therapeutic targets. The available mouse models confirm the pleiotropic action of PP1 in health and diseases.

Keywords: PP1 interacting proteins (PIP); Protein phosphatase 1; human disease-associated phenotypes; mouse genetics; structural reverse genetics.

Fig. 1

Structure of PP1 holoenzymes. Surface representation of the PP1 catalytic domain (center). Indicated are the two metals in the active site of PP1 (red spheres) that lies at the Y-shaped intersection of three substrate-binding grooves; the acidic groove (A), the C-terminal groove (C) and the hydrophobic groove (H). Inhibitory PIP (iPIP) is depicted in yellow, a guiding PIP (gPIP) in blue and substrates in purple. Various interaction sites that can be considered for therapeutic targeting are represented by colored circles as indicated in the inset box. Bended black arrows indicate dephosphorylation of the substrate. PP1 surface structure was made using PyMOL (www.pymol.com). PIPs and substrates are schematically placed on PP1. PP1, Protein Phosphatase 1; PIP, PP1-Interacting Protein. See text for references.

Fig. 2

Schematic representation of domain structure of an inhibitory PIP (iPIP) and a guiding PIP (gPIP). DARPP32 and GM from Mus musculus are depicted on scale. DARPP-32 contains a PP1-anchoring domain (red box) and a PP1-inhibitory domain (yellow box) in its N-terminal third. DARPP32 inhibits PP1 potently after phosphorylation of the PP1-inhibitory domain at threonine 34 residue. GM contains N-terminal a PP1-anchoring and a glycogen-targeting domain, while a second subcellular targeting domain that binds to sarcoplasmic reticulum (SR) is located at its C-terminus. DARPP-32, dopamine and cyclic AMP-regulated phosphoprotein of 32 kDa; GM, skeletal muscle glycogen targeting protein phosphatase 1 regulatory subunit; PIP, PP1-Interacting Protein. See text for references.

Fig. 3

Classification of PP1 and PIPs according their biological functions and their connection to at least one human disease-associated phenotypes. The figure shows PP1 isoforms and PIPs that are linked to specific pathologies reminiscent of several human diseases: cardiovascular systems to heart failure, heart arrhythmia and/or hypertension; behavioural/neurological to drug addiction, schizophrenia, and/or Parkinson's disease, homeostatic/metabolic to type 2 diabetes and/or bile duct hyperplasia; reproductive to male infertility; haematological to thalassemia and respiratory system to SARS-CoV pathogenesis. See text for references. PP1, protein phosphatase 1; PIPs, PP1 interacting proteins; SARS-CoV, severe acute respiratory syndrome coronavirus.