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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human papillomavirus E7 protein is phosphorylated at the two serines in positions 31/32, which are part of a consensus sequence for casein kinase II (CKII). In this study, we have investigated the effect of CKII phosphorylation site mutations, all of which lead to unphosphorylated E7 proteins. The replacement of the two serines by uncharged alanine residues drastically reduced the ability of E7 to cotransform primary cells with ras, whereas negatively charged aspartic acid at the same positions produced only a slight effect. This difference was not reflected in the p105Rb binding or the E2 promoter transactivation capability of these two mutants. Mutations that changed the CKII consensus without altering the serine residues also resulted in a loss of phosphorylation and transformation. This indicated that negative charge at positions 31/32 provided either by phosphorylation or by a negatively charged amino acid is necessary for efficient transformation without significantly affecting p105Rb binding or transactivation.
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PMID:Negative charge at the casein kinase II phosphorylation site is important for transformation but not for Rb protein binding by the E7 protein of human papillomavirus type 16. 205

In order to obtain a peptide retaining its biological activity following microinjection into living cells, we have modified a synthetic peptide [PKi(m)(6-24)], derived from the specific inhibitor protein of the cAMP-dependent protein kinase (A-kinase) in two ways: (1) substitution of the arginine at position 18 for a D-arginine; (2) blockade of the side chain on the C-terminal aspartic acid by a cyclohexyl ester group. In an in vitro assay, PKi(m) has retained a specific inhibitory activity against A-kinase as assessed against six other kinases, with similar efficiency to that of the unmodified PKi(5-24) peptide. Microinjection of PKi(m) into living fibroblasts reveals its capacity to prevent the changes in cell morphology and cytoskeleton induced by drugs which activate endogenous A-kinase, whereas the original PKi peptide failed to do so. This inhibition of A-kinase in vivo by PKi(m) lasts between 4 and 6 h after injection. In light of its effective half-life, this modified peptide opens a route for the use of biologically active peptides in vivo, an approach which has been hampered until now by the exceedingly short half-life of peptides inside living cells. By providing a direct means of inhibiting A-kinase activity for sufficiently long periods to observe effects on cellular functions in living cells, PKi(m) represents a powerful tool in studying the potential role of cAMP-dependent phosphorylation in vivo.
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PMID:Effective intracellular inhibition of the cAMP-dependent protein kinase by microinjection of a modified form of the specific inhibitor peptide PKi in living fibroblasts. 207 Aug 29

The traffic of ions through the kainic acid (KA) receptor/channels present on chick cerebellar glia is modulated by intracellular events likely to involve phosphorylation reactions. The protein carrying the KA binding sites has been isolated from chick cerebellum and shown to be composed of a 49-kDa polypeptide. Its primary structure, established via cDNA cloning, shows the presence of two putative phosphorylation sites. We report here that this 49-kDa polypeptide is a substrate of the cAMP-dependent protein kinase which catalyzes the incorporation of up to 2 mol of phosphate/mol of KA binding site. KA prevents this phosphorylation reaction in a concentration range similar to that needed to activate the KA receptor/channels but higher by 3 orders of magnitude than that needed to saturate the KA binding sites. Kainatergic ligands produce similar effects to those of KA, but 1 mM N-methyl-D-aspartic acid and 1 mM quisqualic acid have no effect. However, 0.01 mM quisqualic acid prevents the inhibitory action of KA. These results raise the possibility that the phosphorylation of KA receptor/channels in their cellular environment is negatively regulated by KA.
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PMID:Phosphorylation of the 49-kDa putative subunit of the chick cerebellar kainate receptor and its regulation by kainatergic ligands. 217 71

Vertebrate photoreceptor cells contain a soluble phosphoprotein, phosducin, which complexes with the beta, gamma subunits of the GTP-binding protein, transducin. Light-induced changes in cyclic nucleotide levels modulate the phosphorylation of phosducin by protein kinase A. The complete amino acid sequence of purified phosducin from bovine retinas was determined by Edman degradation from overlapping polypeptides derived from enzymatic digestion by trypsin and Staphylococcus aureus V8 protease or from chemical degradation by cyanogen bromide. Excluding the unidentified group which blocks the NH2 terminus, phosducin contains 245 amino acids with a calculated molecular weight of 28,185 and isoelectric point of pH 4.5. Phosducin is enriched with acidic and sulfur-containing amino acids, having 32 glutamic acid, 16 aspartic acid, 9 methionine, and 5 cysteine residues. It also contains 24 serine and 8 threonine residues, of which only serine 73 is located within a consensus phosphorylation sequence (-RKMS(P)QV-) for cyclic nucleotide-dependent protein kinase. Secondary structure analysis predicts the presence of 62% alpha-helix, 22% beta-sheet, and 16% random coil, with eight turns. Computer-aided searches of protein data banks revealed no apparent homology to any sequenced protein except that coded by a MEKA cDNA clone (Kuo, C-H., Akiyama, M., and Miki, N. (1989) Mol. Brain Res. 6, 1-10) which deviates from the confirmed phosducin sequence in the last 15 amino acids. Sequence analysis of a cDNA clone for bovine retinal phosducin confirmed that the MEKA clone deviation resulted from an unidentified cDNA guanosine nucleotide, a shifted reading frame and a premature stop codon.
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PMID:Amino acid and cDNA sequence of bovine phosducin, a soluble phosphoprotein from photoreceptor cells. 220 90

cDNAs coding for a plasma membrane Ca2+ pump were isolated from a human teratoma library and sequenced. The translated sequence contained 1,220 amino acids with a calculated molecular weight of 134,683. All regions of functional importance known from other ion-transporting ATPases could be identified. The translated sequence also contained, near the carboxyl terminus, the calmodulin-binding domain and two domains which are very rich in glutamic acid and aspartic acid. These two domains resemble calmodulin somewhat and one of them may play a role in the binding of Ca2+. The enzyme also contains domains rich in serine and threonine, one of which has a sequence matching those of good cAMP-dependent protein kinase substrates. The carboxyl-terminal region is important for regulation by calmodulin, proteolysis, and phosphorylation. Near the amino terminus are two domains which are very rich in lysine and glutamic acid, as well as two domains resembling EF hands, one of which also has some resemblance to calmodulin. Comparison of the cloned sequence with peptide sequences from the erythrocyte Ca2+ pump showed that the two proteins have a very high proportion of identical residues but are not 100% identical, indicating that they represent different isozymes.
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PMID:Complete primary structure of a human plasma membrane Ca2+ pump. 284 59

A library of recombinant bacteriophage was prepared from ts167 avian erythroblastosis virus-transformed erythroid precursor cells (HD6), and integrated proviruses from three distinct genomic loci were isolated. A subclone of one of these proviruses (pAEV1) was shown to confer temperature-sensitive release from transformation of erythroid precursor cells in vitro. The predicted amino acid sequence of the v-erbB polypeptide from the mutant had a single amino acid change when compared with the wild-type parental virus. When the wild-type amino acid was introduced into the temperature-sensitive avian erythroblastosis virus provirus in pAEV1, all erythroid clones produced in vitro were phenotypically wild type. The mutation is a change from a histidine to an aspartic acid in the temperature-sensitive v-erbB polypeptide. It is located in the center of the tyrosine-specific protein kinase domain and corresponds to amino acid position 826 of the human epidermal growth factor receptor sequence.
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PMID:A single amino acid substitution in v-erbB confers a thermolabile phenotype to ts167 avian erythroblastosis virus-transformed erythroid cells. 287 64

The transforming gene product encoded by Moloney murine sarcoma virus clone 124, p37mos, contains a lysine residue (lysine-121) that is conserved among all members of the protein kinase family. This lysine has been shown to be part of a conserved ATP-binding site in both the catalytic subunit of the cAMP-dependent protein kinase and p60v-src. We wished to determine whether this lysine is required for the transforming activity of p37mos. Two site-specific mutations were therefore constructed, which result in the substitution of an aspartic acid or arginine codon in place of the codon for lysine-121. Both mutations abolished the ability of the mos gene to transform cells. These results show that lysine-121 is required for the ability of p37mos to transform cells and provide evidence for an ATP-binding site in p37mos. Furthermore, these results suggest that the conserved lysine residue is specifically involved in the catalytic activity of protein kinases in general.
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PMID:Lysine residue 121 in the proposed ATP-binding site of the v-mos protein is required for transformation. 299 82

Glycogen synthase is a substrate for five distinct protein kinases in skeletal muscle which phosphorylate seven different serine residues on the enzyme. Cyclic-AMP-dependent protein kinase phosphorylates sites 1a, 1b and 2, phosphorylase kinase, site 2, glycogen synthase kinase 3, sites 3a, 3b and 3c, glycogen synthase kinase 4, site 2 and glycogen synthase kinase 5 site 5. Site 2 is seven residues from the N-terminus of glycogen synthase and is located in a cyanogen bromide peptide termed CB1 (apparent Mr = 9000). The other six phosphorylation sites are located in a cyanogen bromide peptide termed CB2 (apparent Mr = 24 000) at the C-terminal end of the molecule. The sequence of the N-terminal 123 residues of peptide CB2, has been completed. Sites 3a, 3b, 3c, 5, 1a and 1b are located at residues 30, 34, 38, 46, 87 and 100 from the N-terminus of CB2 respectively. Site 1a is the next serine residue after site 5. The region surrounding sites 3a, 3b and 3c is very rich in proline residues while that surrounding sites 1a and 1b contains many serine and threonine residues. The 23 residues following site 5 contain 15 aspartic acid and glutamic acid residues, while the region immediately N-terminal to site 1a is very basic. The whole region is remarkably hydrophilic and is the region at which the native enzyme is attacked by proteinases. The sites at which glycogen synthase is cleaved by trypsin, chymotrypsin and thermolysin have been identified. The finding that trypsin cleaves the enzyme C-terminal to site 3c while chymotrypsin cleaves N-terminal to site 3a has formed the basis of a simple procedure for determining the state of phosphorylation of the seven serine residues in vivo [Parker, P.J., Embi, N., Caudwell, F.B., and Cohen, P. (1982) Eur. J. Biochem. 124, 47-55].
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PMID:Multisite phosphorylation of glycogen synthase from rabbit skeletal muscle. Organisation of the seven sites in the polypeptide chain. 680 97

Progression through the cell cycle is catalyzed by cyclin-dependent kinases (CDKs) and is negatively controlled by CDK inhibitors (CDIs). We have isolated a new member of the p21CIP1/p27KIP1 CDI family and named it p57KIP2 to denote its apparent molecular mass and higher similarity to p27KIP1. Three distinct p57 cDNAs were cloned that differ at the start of their open reading frames and correspond to messages generated by the use of distinct splice acceptor sites. p57 is distinguished from p21 and p27 by its unique domain structure. Four distinct domains follow the heterogeneous amino-terminal region and include, in order, a p21/p27-related CDK inhibitory domain, a proline-rich (28% proline) domain, an acidic (36% glutamic or aspartic acid) domain, and a carboxy-terminal nuclear targeting domain that contains a putative CDK phosphorylation site and has sequence similarity to p27 but not to p21. Most of the acidic domain consists of a novel, tandemly repeated 4-amino acid motif. p57 is a potent inhibitor of G1- and S-phase CDKs (cyclin E-cdk2, cyclin D2-cdk4, and cyclin A-cdk2) and, to lesser extent, of the mitotic cyclin B-Cdc2. In mammalian cells, p57 localizes to the nucleus, associates with G1 CDK components, and its overexpression causes a complete cell cycle arrest in G1 phase. In contrast to the widespread expression of p21 and p27 in human tissues, p57 is expressed in a tissue-specific manner, as a 1.5-kb species in placenta and at lower levels in various other tissues and a 7-kb mRNA species observed in skeletal muscle and heart. The expression pattern and unique domain structure of p57 suggest that this CDI may play a specialized role in cell cycle control.
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PMID:Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. 772 83

Cardiac myosin binding protein-C (cardiac MyBP-C, cardiac C protein) belongs to a family of proteins implicated in both regulatory and structural functions of striated muscle. For the cardiac isoform, regulatory phosphorylation in vivo by cAMP-dependent protein kinase (PKA) upon adrenergic stimulation is linked to modulation of cardiac contraction. The sequence of human cardiac MyBP-C now reveals regulatory motifs specific for this isoform. Site-directed mutagenesis identifies a LAGGGRRIS loop in the N-terminal region of cardiac MyBP-C as the key substrate site for phosphorylation by both PKA and a calmodulin-dependent protein kinase associated with the native protein. Phosphorylation of two further sites by PKA is induced by phosphorylation of this isoform-specific site. This phosphorylation switch can be mimicked by aspartic acid instead of phosphoserine. Cardiac MyBP-C is therefore specifically equipped with sensors for adrenergic regulation of cardiac contraction, possibly implicating cardiac MyBP-C in cardiac disease. The gene coding for cardiac MyBP-C has been assigned to the chromosomal location 11p11.2 in humans, and is therefore in a region of physical linkage to subsets of familial hypertrophic cardiomyopathy (FHC). This makes cardiac MyBP-C a candidate gene for chromosome 11-associated FHC.
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PMID:Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction? 774 2


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