Structural basis for protein phosphatase 1 regulation and specificity

Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI, USA  Department of Chemistry, Brown University, Providence, RI, USA  Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA  Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
FEBS Journal (Impact Factor: 4). 01/2012; 280(2). DOI: 10.1111/j.1742-4658.2012.08509.x
Source: PubMed


The ubiquitous serine/threonine protein phosphatase 1 (PP1) regulates diverse, essential cellular processes such as cell cycle progression, protein synthesis, muscle contraction, carbohydrate metabolism, transcription and neuronal signaling. However, the free catalytic subunit of PP1, while an effective enzyme, lacks substrate specificity. Instead, it depends on a diverse set of regulatory proteins (≥ 200) to confer specificity towards distinct substrates. Here, we discuss recent advances in structural studies of PP1 holoenzyme complexes and summarize the new insights these studies have provided into the molecular basis of PP1 regulation and specificity.

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    • "Common with many PP1 regulators, which also show disordered structure particularly within the PP1-binding domain, GADD34 readily and specifically interacts with PP1 to form a functional phosphatase holoenzyme (Figure 2). To do this, GADD34 uses two well-established PP1-anchoring motifs: the canonical RVxF motif found in R85% of PP1 regulators as well as the FF motif, a newly identified motif predicted to be present in 20% of PP1 regulators (Choy et al., 2014; Peti et al., 2013) (Figure 2). Although these motifs provide for tight binding of PP1 by GADD34 they do not account for the unique specificity of the GADD34:PP1 complex as an eIF2a phosphatase. "
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    ABSTRACT: The attenuation of protein synthesis via the phosphorylation of eIF2α is a major stress response of all eukaryotic cells. The growth-arrest- and DNA-damage-induced transcript 34 (GADD34) bound to the serine/threonine protein phosphatase 1 (PP1) is the necessary eIF2α phosphatase complex that returns mammalian cells to normal protein synthesis following stress. The molecular basis by which GADD34 recruits PP1 and its substrate eIF2α are not fully understood, hindering our understanding of the remarkable selectivity of the GADD34:PP1 phosphatase for eIF2α. Here, we report detailed structural and functional analyses of the GADD34:PP1 holoenzyme and its recruitment of eIF2α. The data highlight independent interactions of PP1 and eIF2α with GADD34, demonstrating that GADD34 functions as a scaffold both in vitro and in cells. This work greatly enhances our molecular understanding of a major cellular eIF2α phosphatase and establishes the foundation for future translational work. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Cell Reports
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    • "PHACTR1 is highest expressed in human heart and brain [77] and is a member of a family of proteins that bind actin and interact with protein phosphatase 1 (PP1) [78]. PP1 is an ubiquitous enzyme, regulating essential cellular processes such as cell cycle progression, protein synthesis, muscle contraction, carbohydrate metabolism, transcription, and neuronal signaling (reviewed in [79]). For PHACTR1, a role in cell migration, motility and invasiveness of breast cancer, and melanoma tumor cells was described [80,81]. "
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    ABSTRACT: Since 2007, genome-wide association studies (GWAS) have led to the identification of numerous loci of atherosclerotic cardiovascular disease. The majority of these loci harbor genes previously not known to be involved in atherogenesis. In this review, we summarize the recent progress in understanding the pathophysiology of genetic variants in atherosclerosis. Fifty-eight loci with P < 10 have been identified in GWAS for coronary heart disease and myocardial infarction. Of these, 23 loci (40%) overlap with GWAS loci of classical risk factors such as lipids, blood pressure, and diabetes mellitus, suggesting a potential causal relation. The vast majority of the remaining 35 loci (60%) are at genomic regions where the mechanism in atherogenesis is unclear. Loci most frequently found in independent GWAS were at Chr9p21.3 (ANRIL/CDKN2B-AS1), Chr6p24.1 (PHACTR1), and Chr1p13.3 (CELSR2, PSRC1, MYBPHL, SORT1). Recent work suggests that Chr9p21.3 exerts its effects through epigenetic regulation of target genes, whereas mechanisms at Chr6p24.1 remain obscure, and Chr1p13.3 affects plasma LDL cholesterol. Novel GWAS loci indicate that our understanding of atherosclerosis is limited and implicate a role of hitherto unknown mechanisms, such as epigenetic gene regulation in atherogenesis.
    Full-text · Article · Oct 2013 · Current opinion in lipidology
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    • "Structures with I2 Tyr149 displaced from the second metal site came from piX and piXp trajectories (Table S3). Deprotonation of PP1 His66 to a δ-protonated residue allowed it to coordinate Mn 2+ B (the second Mn 2+ ) via NE2 like all crystallographic PP1 structures [4]. The average of coordinating ligand positions (PP1 Asp64, His66, and Asp92) assigned Mn 2+ B coordinates. "
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    ABSTRACT: Phosphorylation regulates activity of many proteins; however, atomic level details are known for very few examples. Inhibitor-2 (I2) squelches the ubiquitous protein phosphatase-1 (PP1) enzyme activity by blocking access to the metal-containing active site. I2 Thr74 phosphorylation results in PP1 activation without I2 dissociation from the PP1-I2 complex. The dynamic disordered structure of the 73-residue segment of I2 containing Thr74, prevented visualization by X-ray crystallography of PP1-I2. In this work, I generated structures of this segment using simulated annealing to NMR restraints, fused them to the crystallographic PP1-I2 coordinates, and used molecular dynamics to study the impact of Thr74 phosphorylation on structural alterations leading to PP1 activation. Frequencies of I2 Tyr149 displacement from the PP1 active site, rotation of the phenolic Tyr149 side chain to prevent its reinsertion, and repositioning the I2 inhibitory helix to expose the PP1 active site to solvent and substrates significantly increased upon I2 Thr74 phosphorylation. After these steps, a second metal bound to produce PP1-Mn(2)-I2, which held the phosphorylated form of I2 to its active site less tightly than it held dephosphorylated I2. I2 Thr74 lies on the edge of variable dynamic communities of residues where it forms various allosteric pathways that induce motions at the PP1 active site 20Å away. These molecular dynamics simulations show how an unstructured region of I2 can harness enhanced rapid movements around phosphorylated Thr74 to pry I2 residues away from the PP1 active site in early steps of PP1-I2 activation.
    Full-text · Article · Sep 2012 · Biochimica et Biophysica Acta
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