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)

Regulation of various metabolic processes occurs by the phosphorylation/dephosphorylation of enzymes. Both the protein kinases that catalyze the phosphorylations and the protein phosphatases that catalyze the dephosphorylations display relatively broad specificity, reacting with a number of distinct sites in target enzymes. In this way changes in the activity of a particular kinase or phosphatase can cause coordinated and pleiotropic responses. However, the kinases and phosphatases do not exhibit a one-to-one correspondence in their reactions. Residues at different positions may be phosphorylated by a single kinase, yet dephosphorylated by different individual phosphatases. Conversely, sites which are substrates for different individual kinases may be dephosphorylated by a single phosphatase. In exploring the molecular basis for these differences this article shows that whereas kinases react with specific primary structures that often times appear as beta bends, the phosphatases recognize higher order structure, less strictly ruled by amino acid sequence surrounding the phosphorylated site. The differences, seen in the ability of these enzymes to utilize synthetic peptide substrates, might be rationalized in terms of function. Kinases need protruding segments of structure that can be enwrapped to exclude water, thereby minimizing ATP hydrolysis and enhancing phosphotransferase activity. On the other hand phosphatases are hydrolytic enzymes that may operate especially well on protein interfaces. Hydrolytic action often measured with p-nitrophenylphosphate is not necessarily indicative of a protein phosphatase and consideration of the mechanism reveals why this substrate can be misleading.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular basis for substrate specificity of protein kinases and phosphatases. 301 39

FHA domains adopt a beta-sandwich fold with 11 strands. The first evidence of partially unfolded forms of a beta-sandwich is derived from native-state hydrogen exchange (NHX) of the forkhead-associated (FHA) domain from kinase-associated protein phosphatase from Arabidopsis. The folding kinetics of this FHA domain indicate that EX2 behavior prevails at pH 6.3. In the chevron plot, rollover in the folding arm and bends in the unfolding arm suggest folding intermediates. NHX of this FHA domain suggests a core of six most stable beta-strands and two loops, characterized by rare global unfolding events. Flanking this stable core are beta-strands and recognition loops with less stability, termed subglobal motifs. These suggest partially unfolded forms (near-native intermediates) with two levels of stability. The spatial separation of the subglobal motifs on the flanks suggests possible parallelism in their folding as additional beta-strands align with the stable core of six strands. Intermediates may contribute to differences in stabilities and m-values suggested by NHX or kinetics relative to chemical denaturation. Residual structure in the unfolded regime is suggested by superprotection of beta-strand 6 and by GdmCl-dependence of adjustments in amide NMR spectra and residual optical signal. The global folding stability depends strongly on pH, with at least 3 kcal/mol more stability at pH 7.3 than at pH 6.3. This FHA domain is hypothesized to fold progressively with initial hydrophobic collapse of its stable six-stranded core followed by addition of less stable flanking beta-strands and ordering of recognition loops.
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PMID:Partially unfolded forms and non-two-state folding of a beta-sandwich: FHA domain from Arabidopsis receptor kinase-associated protein phosphatase. 1700 79

Better understanding of the physiological mechanisms and neurological symptoms involved in the development of decompression sickness could contribute to improvements of diving procedures. The main objective of the present study was to determine effects on the brain proteome of fast decompression (1 bar/20 s) compared to controls (1 bar/10 min) after heliox saturation diving, using rats in a model system. The protein S100B, considered a biomarker for brain injury, was not significantly different in serum samples from one week before, immediately after, and one week after the dive. Alterations in the rat brain proteome due to fast decompression were investigated using both iontrap and orbitrap LC-MS, and 967 and 1062 proteins were quantified, respectively. Based on the significantly regulated proteins in the iontrap (56) and orbitrap (128) datasets, the networks "synaptic vesicle fusion and recycling in nerve terminals" and "translation initiation" were significantly enriched in a system biological database analysis (Metacore). Ribosomal proteins (RLA2, RS10) and the proteins hippocalcin-like protein 4 and proteasome subunit beta type-7 were significantly upregulated in both datasets. The heat shock protein 105 kDa, Rho-associated protein kinase 2 and Dynamin-1 were significantly downregulated in both datasets. Another main effect of hyperbaric fast decompression in our experiment is inhibition of endocytosis and stimulation of exocytosis of vesicles in the presynaptic nerve terminal. In addition, fast decompression affected several proteins taking parts in these two main mechanisms of synaptic strength, especially alteration in CDK5/calcineurin are associated with a broad range of neurological disorders. In summary, fast decompression after heliox saturation affected the brain proteome in a rat model for diving, potentially disturbing protein homeostasis, e.g. in synaptic vesicles, and destabilizing cytoskeletal components. Data are available via ProteomeXchange with identifier PXD006349.
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PMID:Fast hyperbaric decompression after heliox saturation altered the brain proteome in rats. 2897 37