Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the isolation of the first yeast protein phosphatase genes in 1989, much progress has been made in understanding this important group of proteins. Yeast contain genes encoding all the major types of protein phosphatase found in higher eukaryotes and the ability to use genetic approaches will complement the wealth of biochemical information available from other systems. This review will summarize recent progress in understanding the structure, function and regulation of the PPP family of protein serine-threonine phosphatases, concentrating on the budding yeast Saccharomyces cerevisiae.
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PMID:Yeast protein serine/threonine phosphatases: multiple roles and diverse regulation. 912 67

Eukaryotic protein phosphatases are structurally and functionally diverse enzymes that are represented by three distinct gene families. Two of these, the PPP and PPM families, dephosphorylate phosphoserine and phosphothreonine residues, whereas the protein tyrosine phosphatases (PTPs) dephosphorylate phosphotyrosine amino acids. A subfamily of the PTPs, the dual-specificity phosphatases, dephosphorylate all three phosphoamino acids. Within each family, the catalytic domains are highly conserved, with functional diversity endowed by regulatory domains and subunits. The protein Ser/Thr phosphatases are metalloenzymes and dephosphorylate their substrates in a single reaction step using a metal-activated nucleophilic water molecule. In contrast, the PTPs catalyze dephosphorylation by use of a cysteinyl-phosphate enzyme intermediate. The crystal structures of a number of protein phosphatases have been determined, enabling us to understand their catalytic mechanisms and the basis for substrate recognition and to begin to provide insights into molecular mechanisms of protein phosphatase regulation.
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PMID:The structure and mechanism of protein phosphatases: insights into catalysis and regulation. 964 65

Inspection of the genomes for the bacteria Bacillus subtilis 168, Borrelia burgdorferi B31, Escherichia coli K-12, Haemophilus influenzae KW20, Helicobacter pylori 26695, Mycoplasma genitalium G-37, and Synechocystis sp PCC 6803 and for the archaeons Archaeoglobus fulgidus VC-16 DSM4304, Methanobacterium thermoautotrophicum delta H, and Methanococcus jannaschii DSM2661 revealed that each contains at least one ORF whose predicted product displays sequence features characteristic of eukaryote-like protein-serine/threonine/tyrosine kinases and protein-serine/threonine/tyrosine phosphatases. Orthologs for all four major protein phosphatase families (PPP, PPM, conventional PTP, and low molecular weight PTP) were present in the bacteria surveyed, but not all strains contained all types. The three archaeons surveyed lacked recognizable homologs of the PPM family of eukaryotic protein-serine/threonine phosphatases; and only two prokaryotes were found to contain ORFs for potential phosphatases from all four major families. Intriguingly, our searches revealed a potential ancestral link between the catalytic subunits of microbial arsenate reductases and the protein-tyrosine phosphatases; they share similar ligands (arsenate versus phosphate) and features of their catalytic mechanism (formation of arseno-versus phospho-cysteinyl intermediates). It appears that all prokaryotic organisms, at one time, contained the genetic information necessary to construct protein phosphorylation-dephosphorylation networks that target serine, threonine, and/or tyrosine residues on proteins. However, the potential for functional redundancy among the four protein phosphatase families has led many prokaryotic organisms to discard one, two, or three of the four.
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PMID:The serine, threonine, and/or tyrosine-specific protein kinases and protein phosphatases of prokaryotic organisms: a family portrait. 986 22

Prokaryotes contain at least five distinct families of protein O-phosphatases, including AceK, the chimeric isocitrate dehydrogenase kinase/phosphatase, and four protein phosphatase families first identified and characterized in Eukaryotes. The latter consist of the PPP and PPM families of protein-serine/threonine phosphatases, and the low molecular weight and conventional families of protein-tyrosine phosphatases. Prokaryotic protein O-phosphatases participate in the regulation of metabolic processes and the transduction of environmental signals. Certain pathogenic bacteria employ protein-tyrosine phosphatases as virulence factors, injecting them into host cells where they enzymatically perturb the phosphorylation state of proteins therein. While our understanding of protein O-phosphorylation events in Prokaryotes only now is emerging from its infancy, their phylogenetic diversity and malleability to genetic manipulation render these "simple'" organisms powerful vehicles for answering fundamental questions concerning the origins and evolution of this key biological regulatory mechanism.
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PMID:Life among the primitives: protein O-phosphatases in prokaryotes. 1007 42

A novel protein phosphatase cDNA of the PPP superfamily was identified from the malaria parasite, Plasmodium falciparum (Pf), and tentatively named PfPPJ. The predicted primary structure of the phosphatase contained all the known conserved motifs of the PPP superfamily essential for catalytic activity. The enzyme was specific for dephosphorylation of phosphoserine and phosphothreonine residues with very little activity against phosphotyrosine residues. However, the sequence at its C-terminal end was unique, and was consistent with its resistance to the classical PP2A-specific inhibitors such as okadaic acid and microcystin-LR, and the PP1-specific inhibitor, mammalian heat-stable inhibitor-2 (I-2). Even the catalytic core of PfPPJ had a sequence substantially different from the other PPPs such that PfPPJ could be placed in an apparently separate phylogenetic branch. At 294 amino acids residues, PfPPJ was one of the smallest okadaic acid-resistant PPP phosphatases known. By Northern blot analysis, the expression of the PfPPJ mRNA showed the following pattern: schizont > ring > trophozoite, which closely paralleled the expression of the protein, as determined by immunofluorescence. Together, these results suggested a parasitic stage-specific transcriptional regulation of this novel and potentially unique protozoan phosphatase.
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PMID:Characterization of a novel serine/threonine protein phosphatase (PfPPJ) from the malaria parasite, Plasmodium falciparum. 1137 37

PP7, a recently identified protein Ser/Thr phosphatase of the PPP family distantly related to phosphatases PP5/PPT and PPEF/rdgC, was purified from cauliflower extracts to apparent homogeneity. Purified cauliflower PP7 and recombinant PP7 expressed in Escherichia coli exhibit light absorption in the visible range with a maximum at approximately 430 nm. Under nonreducing conditions, native PP7 exists as a mixture of monomer with an intramolecular disulfide bridge, disulfide-linked homodimer, and possibly disulfide-linked complexes with potential partner proteins. The activity of recombinant Arabidopsis thaliana PP7 is reversibly regulated by redox agents. The results demonstrate the existence of PP7 protein in planta and suggest a possibility of redox regulation of this protein phosphatase.
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PMID:Purification of plant protein phosphatase PP7 and evidence for its redox regulation. 1171 63

Salmonella enterica serovar Typhimurium requires Mn(2+), but only a few Mn(2+)-dependent enzymes have been identified from bacteria. To characterize Mn(2+)-dependent enzymes from serovar Typhimurium, two putative PPP-family protein phosphatase genes were cloned from serovar Typhimurium and named prpA and prpB. Their DNA-derived amino acid sequences showed 61% identity to the corresponding Escherichia coli proteins and 41% identity to each other. Each phosphatase was expressed in E. coli and purified to near electrophoretic homogeneity. Both PrpA and PrpB absolutely required a divalent metal for activity. As with other phosphatases of this class, Mn(2+) had the highest affinity and stimulated the greatest activity. The apparent K(a) of PrpA for Mn(2+) of 65 microM was comparable to that for other bacterial phosphatases, but PrpB had a much higher affinity for Mn(2+) (1.3 microM). The pH optima were pH 6.5 for PrpA and pH 8 for PrpB, while the optimal temperatures were 45 to 55 degrees C for PrpA and 30 to 37 degrees C for PrpB. Each phosphatase could hydrolyze phosphorylated serine, threonine, or tyrosine residues, but their relative specific activities varied with the specific substrate tested. These differences suggest that each phosphatase is used by serovar Typhimurium under different growth or environmental conditions such as temperature or acidity.
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PMID:The PPP-family protein phosphatases PrpA and PrpB of Salmonella enterica serovar Typhimurium possess distinct biochemical properties. 1171 62

This report describes the presence in plants of protein Ser/Thr phosphatases of the PPP family, homologous to PfPPalpha phosphatase from Plasmodium falciparum. Like PfPPalpha, they possess large N-terminal domains and catalytic domains that are more closely related to the protein phosphatase 1 group. The N-terminal domains of PfPPalpha and its plant homologues contain tandem kelch-like repeats, not previously identified in any protein phosphatases, suggesting that the N-terminal domains may form beta-propeller structures mediating protein-protein interactions. We therefore suggest that this novel phosphatase group be designated as PPKLs for protein phosphatases with kelch-like repeat domains. Four PPKL isoforms are encoded in the Arabidopsis thaliana genome, of which at least three are expressed. PPKLs appear to be ubiquitous in Viridiplantae. The existence of a protein phosphatase group shared by Viridiplantae and Apicomplexa, but not other eukaryotes, is in line with the theory of the origin of Apicomplexa by endosymbiosis of nonphotosynthetic eukaryotes with red algae.
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PMID:Protein Ser/Thr phosphatases with kelch-like repeat domains. 1203 55

Transcription by RNA polymerase-II (RNAPII) is controlled by multisite phosphorylation of the heptapeptide repeats in the C-terminal domain (CTD) of the largest subunit. Phosphorylation of CTD is mediated by the cyclin-dependent protein kinases Cdk7 and Cdk9, whereas protein serine/threonine phosphatase FCP1 dephosphorylates CTD. We have recently reported that human immunodeficiency virus-1 (HIV-1) transcription is positively regulated by protein phosphatase-1 (PP1) and that PP1 dephosphorylates recombinant CTD. Here, we provide further evidence that PP1 can dephosphorylate RNAPII CTD. In vitro, PP1 dephosphorylated recombinant CTD as well as purified RNAPII CTD. HeLa nuclear extracts were found to contain a species of PP1 that dephosphorylates both serine 2 and serine 5 of the heptapeptide repeats. In nuclear extracts, PP1 and FCP1 contributed roughly equally to the dephosphorylation of serine 2. PP1 co-purified with RNAPII by gel filtration and associated with RNAPII on immunoaffinity columns prepared with anti-CTD antibodies. In cultured cells treated with CTD kinase inhibitors, the dephosphorylation of RNAPII on serine 2 was inhibited by 45% by preincubation with okadaic acid, which inhibits phosphatases of PPP family, including PP1 but not FCP1. Our data demonstrate that RNAPII CTD is dephosphorylated by PP1 in vitro and by PPP-type phosphatase, distinct from FCP1, in vivo.
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PMID:Protein phosphatase-1 dephosphorylates the C-terminal domain of RNA polymerase-II. 1218 79

The cellular localization of the 35 kDa, low molecular mass acid metallophosphatase (LMW AcPase) from the frog (Rana esculenta) liver and its activity towards P-Ser and P-Tyr phosphorylated peptides were studied. This enzyme was localized to the cytoplasm of hepatocytes but did not appear in other cells of liver tissue (endothelium, macrophages, blood cells). This LMW AcPase does not display activity towards (32)P-phosphorylase a under conditions standard for the enzymes of PPP family. Proteins containing P-Ser: rabbit (32)P-phosphorylasea and phosvitin are hydrolysed only at acidic pH and are poor substrates for this enzyme. The frog AcPase is not inhibited by okadaic acid and F(-) ions, the Ser/Thr protein phosphatase inhibitors. Moreover, the frog enzyme does not cross-react with specific antisera directed against N-terminal fragment of human PP2A and C-terminal conserved fragment of the eukaryotic PP2A catalytic subunits. These results exclude LMW AcPase from belonging to Ser/Thr protein phosphatases: PP1c or PP2Ac. In addition to P-Tyr, this enzyme hydrolyses efficiently at acidic pH P-Tyr phosphorylated peptides (hirudin and gastrin fragments). K(m) value for the hirudin fragment (7.55 +/- 1.59 x 10(-6) M) is 2-3 orders of magnitude lower in comparison with other substrates tested. The enzyme is inhibited competitively by typical inhibitors of protein tyrosine phosphatases (PTPases): sodium orthovanadate, molybdate and tungstate. These results may suggest that the LMW AcPase of frog liver can act as PTPase in vivo. A different cellular localization and different response to inhibition by tetrahedral oxyanions (molybdate, vanadate and tungstate) provide further evidence that LMW AcPase of frog liver is distinct from the mammalian tartrate-resistant acid phosphatases.
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PMID:The 35 kDa acid metallophosphatase of the frog Rana esculenta liver: studies on its cellular localization and protein phosphatase activity. 1283 81


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