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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    • "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.
    Current opinion in lipidology 10/2013; 24(5):410-8. DOI:10.1097/MOL.0b013e3283654e7c · 5.66 Impact Factor
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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.
    Biochimica et Biophysica Acta 09/2012; 1834(1). DOI:10.1016/j.bbapap.2012.09.003 · 4.66 Impact Factor
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    • "These observations begin to explain the striking diversity of PP1 holoenzymes, each of which may form a truly unique enzyme with distinctive properties. This is made even more intriguing by the fact that the number of identified PP1-targeting proteins ($200) is still increasing (Bollen et al., 2010; Hendrickx et al., 2009; Peti et al., 2012). If the diversity of interactions observed for PP1 is conserved across ser/thr phosphatases, it would allow the $40 ser/thr protein phosphatases to form hundreds of unique holoenzymes, ensuring that they are as specific as the 428 known ser/thr protein kinases. "
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    ABSTRACT: Regulation of protein phosphatase 1 (PP1) is controlled by a diverse array of regulatory proteins. However, how these proteins direct PP1 specificity is not well understood. More than one-third of the nuclear pool of PP1 forms a holoenzyme with the nuclear inhibitor of PP1, NIPP1, to regulate chromatin remodeling, among other essential biological functions. Here, we show that the PP1-binding domain of NIPP1 is an intrinsically disordered protein, which binds PP1 in an unexpected manner. NIPP1 forms an α helix that engages PP1 at a unique interaction site, using polar rather than hydrophobic contacts. Importantly, the structure also reveals a shared PP1 interaction site outside of the RVxF motif, the ΦΦ motif. Finally, we show that NIPP1:PP1 substrate selectivity is determined by altered electrostatics and enhanced substrate localization. Together, our results provide the molecular basis by which NIPP1 directs PP1 substrate specificity in the nucleus.
    Structure 08/2012; 20(10):1746-56. DOI:10.1016/j.str.2012.08.003 · 5.62 Impact Factor
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