Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The virulence functions of Yersinia enterocolitica include the pYV-encoded Yop proteins and YadA adhesin as well as the chromosome-encoded enterotoxin, Yst. The yop and yadA genes form a temperature-activated regulon controlled by the transcriptional activator VirF. Gene virF, also localized on pYV, is itself thermoinduced in the absence of other pYV genes. The enterotoxin yst gene is silent in some collection strains including strain W22703. This paper describes two Tn5-Tc1 chromosomal insertion mutants of W22703 transcribing virF, and hence the yop and yadA genes, at low temperature. These mutants also resumed their production of Yst, with its typical temperature dependence. Both mutations were insertions in the same gene called ymoA for 'Yersinia modulator'. The cloned ymoA gene fully complemented the two mutations. Several properties of the mutants suggest that ymoA encodes a histone-like protein. According to the nucleic acid sequence, the product of ymoA is an 8064 Da protein rich in aspartic acid (9%), glutamic acid (9%) and lysine (10.5%), but the predicted amino acid sequence shows no similarity with any described histone-like protein. This work supports recent reports which propose a role for DNA topology and bacterial chromatin structure in thermoregulation of virulence functions.
Mol Microbiol 1991 May
PMID:ymoA, a Yersinia enterocolitica chromosomal gene modulating the expression of virulence functions. 195 83

The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of the genomic organization of the corresponding gene has enabled us to study androgen receptors in subjects with the clinical manifestation of androgen insensitivity and in a human prostate carcinoma cell line (LNCaP). Using PCR amplification, subcloning and sequencing of exons 2-8, we identified a G----T mutation in the androgen receptor gene of a subject with the complete form of androgen insensitivity, which inactivates the splice donor site at the exon 4/intron 4 boundary. This mutation causes the activation of a cryptic splice donor site in exon 4, which results in the deletion of 41 amino acids from the steroid binding domain. In two other independently arising cases we identified two different nucleotide alterations in codon 686 (GAC; aspartic acid) located in exon 4. One mutation (G----C) results in an aspartic acid----histidine substitution (with negligible androgen binding), whereas the other mutation (G----A) leads to an aspartic acid----asparagine substitution (normal androgen binding, but a rapidly dissociating androgen receptor complex). Sequence analysis of the androgen receptor in human LNCaP-cells (lymph node carcinoma of the prostate) revealed a point mutation (A----G) in codon 868 in exon 8 resulting in the substitution of threonine by alanine. This mutation is the cause of the altered steroid binding specificity of the LNCaP-cell androgen receptor. The functional consequences of the observed mutations with respect to protein expression, specific ligand binding and transcriptional activation, were established after transient expression of the mutant receptors in COS and HeLa cells. These findings illustrate that functional errors in the human androgen receptor have an enormous impact on phenotype and fertility.
J Steroid Biochem Mol Biol 1991
PMID:Androgen receptor abnormalities. 195 38

A 23-kDa (p23k) rat brain protein was stereospecifically eluted from a 14 beta-bromoacetamidomorphine affinity column, purified to apparent homogeneity by reverse phase HPLC, and partially sequenced. Three degenerate oligodeoxynucleotide probes were synthesized based on this partial amino acid sequence. A rat brain cDNA library was screened using these probes, and a full-length cDNA was isolated. The deduced protein, 187 amino acids long, is rich in glutamic and aspartic acid residues, endowing p23k with a net negative charge at neutral pH. The protein lacks a signal sequence as well as any transmembrane domains. Based on predictions of secondary structure, p23k is a globular protein composed of 30% alpha-helices and 18% beta-pleated sheets. Northern blot analysis revealed p23k transcripts in rat brain, liver, and the mouse x rat neuroblastoma-glioma NG108-14 cell line. Although not an opioid receptor itself, this protein may be associated with such a receptor or be related to a protein that has been shown to be cross-linked to the opioid peptide beta-endorphin.
Mol Endocrinol 1990 Sep
PMID:Purification, cloning, and tissue distribution of a 23-kDa rat protein isolated by morphine affinity chromatography. 197 48

The gene for ricin toxin A chain was modified by site-specific mutagenesis to change arginine 180 to alanine, glutamine, methionine, lysine, or histidine. Separately, glutamic acid 177 was changed to alanine and glutamic acid 208 was changed to aspartic acid. Both the wild-type and mutant proteins were expressed in Escherichia coli and, when soluble, purified and tested quantitatively for enzyme activity. A positive charge at position 180 was found necessary for solubility of the protein and for enzyme activity. Similarly, a negative charge with a proper geometry in the vicinity of position 177 was critical for ricin toxin A chain catalysis. When glutamic acid 177 was converted to alanine, nearby glutamic acid 208 could largely substitute for it. This observation provided valuable structural information concerning the nature of second-site mutations.
Mol Cell Biol 1990 Dec
PMID:Role of arginine 180 and glutamic acid 177 of ricin toxin A chain in enzymatic inactivation of ribosomes. 197 25

A yeast nuclear gene, designated MSK1, has been selected from a yeast genomic library by transformation of a respiratory deficient mutant impaired in acylation of mitochondrial lysine tRNA. This gene confers a respiratory competent phenotype and restores the mutant's ability to acylate the mitochondrial lysine tRNA. The amino acid sequence of the protein encoded by MSK1 is homologous to yeast cytoplasmic lysyl-tRNA synthetase and to the product of the herC gene, which has recently been suggested to code for the Escherichia coli enzyme. These observations indicate that MSK1 codes for the lysyl-tRNA synthetase of yeast mitochondria. Several regions of high primary sequence conservation have been identified in the bacterial and yeast lysyl-tRNA synthetases. These domains are also present in the aspartyl- and asparaginyl-tRNA synthetases, further confirming the notion that all three present-day enzymes originated from a common ancestral gene. The most conserved domain, located near the carboxyl terminal ends of this group of synthetases is characterized by a cluster of glycines and is also highly homologous to the carboxyl-terminal region of the E. coli ammonia-dependent asparagine synthetase. A catalytic function of the carboxyl terminal domain is indicated by in vitro mutagenesis of the yeast mitochondrial lysyl-tRNA synthetase. Replacement of any one of three glycine residues by alanine and in one case by aspartic acid completely suppresses the activity of the enzymes, as evidenced by the inability of the mutant genes to complement an msk1 mutant, even when present in high copy. Other mutations result in partial loss of activity. Only one glycine replacement affects the stability of the protein in vivo. The observed presence of a homologous domain in asparagine synthetase, which, like the aminoacyl-tRNA synthetases, catalyzes the formation of an aminoacyladenylate, suggests that the glycine-rich sequence is part of a catalytic site involved in binding of ATP and of the aminoacyladenylate intermediate.
J Mol Biol 1991 Apr 05
PMID:Structure and evolution of a group of related aminoacyl-tRNA synthetases. 201 46

The Saccharomyces cerevisiae PUT3 gene encodes a transcriptional activator that binds to DNA sequences in the promoters of the proline utilization genes and is required for the basal and induced expression of the enzymes of this pathway. The sequence of the wild-type PUT3 gene revealed the presence of one large open reading frame capable of encoding a 979-amino-acid protein. The protein contains amino-terminal basic and cysteine-rich domains homologous to the DNA-binding motifs of other yeast transcriptional activators. Adjacent to these domains is an acidic domain with a net charge of -17. A second acidic domain with a net charge of -29 is located at the carboxy terminus. The midsection of the PUT3 protein has homology to other activators including GAL4, LAC9, PPR1, and PDR1. Mutations in PUT3 causing aberrant (either constitutive or noninducible) expression of target genes in this system have been analyzed. One activator-defective and seven activator-constitutive PUT3 alleles have been retrieved from the genome and sequenced to determine the nucleotide changes responsible for the altered function of the protein. The activator-defective mutation is a single nucleotide change within codon 409, replacing glycine with aspartic acid. One activator-constitutive mutation is a nucleotide change at codon 683, substituting phenylalanine for serine. The remaining constitutive mutations resulted in amino acid substitutions or truncations of the protein within the carboxy-terminal 76 codons. Mechanisms for regulating the activation function of the PUT3 protein are discussed.
Mol Cell Biol 1991 May
PMID:Analysis of constitutive and noninducible mutations of the PUT3 transcriptional activator. 201 67

Attachment of cells to extracellular matrix (ECM) plays an important role in the regulation of cell growth and differentiated function. We hypothesized that bronchial epithelial cells preferentially attach to ECM proteins and utilize specific receptors for ECM proteins. Bronchial epithelial cells were obtained from bovine lung by protease digestion. Both freshly isolated and cultured bronchial epithelial cells were plated onto plastic petri dishes coated with bovine serum albumin, type I collagen, type IV collagen, fibronectin, laminin, ECM synthesized by cultured bronchial epithelial cells, or uncoated. Freshly isolated cells demonstrated significant attachment to ECM but weak attachment to other matrix proteins. Cultured bronchial epithelial cells attached well to ECM; however, they had relatively increased attachment to type I collagen, type IV collagen, fibronectin, and laminin compared to freshly isolated cells. To determine whether the attachment of bronchial epithelial cells is arginine-glycine-aspartic acid (RGD)-mediated, an RGD-containing peptide known to block attachment mediated by many integrin receptors was added to the media (400 micrograms/ml). There was no inhibition of attachment of freshly isolated cells; however, there was significant but not complete inhibition of the attachment of the cultured cells to type IV collagen, laminin, and fibronectin, but not to type I collagen or ECM. Thus, freshly isolated bronchial epithelial cells readily adhere to ECM, and the attachment does not appear to be mediated by RGD-dependent receptors. Cultured bronchial epithelial cells demonstrate increased attachment to component proteins of ECM, and this attachment is, in part, to RGD-dependent receptors.
Am J Respir Cell Mol Biol 1991 May
PMID:Attachment characteristics of bovine bronchial epithelial cells to extracellular matrix components. 202 81

Non-beta-lactamase-producing, penicillin-resistant strains of Neisseria gonorrhoeae (CMRNG strains) produce altered forms of penicillin-binding protein 2 (PBP2) that have decreased affinity for penicillin. A feature of PBP2 from all CMRNG strains is the presence of an additional residue (Asp-345A) that is absent from PBP2 of penicillin-sensitive strains. The role of the additional aspartic acid residue in the decreased affinity of PBP2 is unclear as PBP2 of all previously examined CMRNG strains possess several other amino acid sequence alterations, in addition to the insertion of Asp-345A, compared to PBP2 of penicillin-sensitive strains. Site-directed mutagenesis has been used to insert the Asp-345A codon into the penA gene from a penicillin-sensitive gonococcus. The resulting penA gene expressed an altered form of PBP2 that had a decreased affinity for benzylpenicillin and was able to transform a penicillin-sensitive strain of N. gonorrhoeae to an increased level of resistance to benzylpenicillin. Insertion of amino acids other than aspartic acid did not produce forms of PBP2 that provided increased resistance to penicillin. Removal of the Asp-345A codon from the penA gene of a CMRNG strain reduced its ability to transform a penicillin-sensitive strain to an increased level of penicillin resistance. The reduction in the affinity of PBP2 in CMRNG strains is therefore largely, although not exclusively, due to the insertion of Asp-345A. Clinical isolates that produce altered forms of PBP2 that differ from that of penicillin-sensitive strains only in the insertion of Asp-345A have been identified.
Mol Microbiol 1990 Jun
PMID:Insertion of an extra amino acid is the main cause of the low affinity of penicillin-binding protein 2 in penicillin-resistant strains of Neisseria gonorrhoeae. 212 May 42

DL-2-Amino-3-phosphonopropionic acid, a phosphonate-substituted derivative of aspartic acid, has been shown to be an inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis in rat brain slices. In this study, the enantiomers of 2-amino-3-phosphonopropionic acid were synthesized and used to further characterize the stereoselectivity and mechanism of interaction of this compound for inhibiting phosphoinositide-coupled (metabotropic) excitatory amino acid receptors. L-2-Amino-3-phosphonopropionic acid was 3-5 times more potent than D-2-amino-3-phosphonopropionic acid as an inhibitor of ibotenate-stimulated [3H]inositol monophosphate formation in slices of the rat hippocampus or quisqualate-stimulated [3H]inositol monophosphate formation in neonatal rat cerebral cortical slices. Carbachol-stimulated phosphoinositide hydrolysis was not inhibited by L-2-amino-3-phosphonopropionic acid, and L-2-amino-3-phosphonopropionic acid had no appreciable affinity for ionotropic excitatory amino acid receptors at concentrations required to inhibit metabotropic excitatory amino acid responses. The inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid on phosphoinositide hydrolysis were not competitive, because they could not be surmounted by increasing concentrations of ibotenate or quisqualate. L-2-Amino-3-phosphonopropionic acid inhibition also could not be prevented by washing the tissue before incubation with ibotenate. Thus, L-2-amino-3-phosphonopropionic acid is a stereoselective inhibitor of metabotropic excitatory amino acid receptors with little affinity for ionotropic receptors. However, the inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid were not readily reversed, and the site at which they act to inhibit metabotropic excitatory amino acid receptors remains to be determined.
Mol Pharmacol 1990 Aug
PMID:Stereoselectivity and mode of inhibition of phosphoinositide-coupled excitatory amino acid receptors by 2-amino-3-phosphonopropionic acid. 216 2

Mouse mammary epithelial cells can be transformed in primary cultures to preneoplastic and neoplastic states when treated with N-methyl-N-nitrosourea (MNU). Mammary carcinomas arising from MNU-induced hyperplastic alveolar nodules (a type of mouse mammary preneoplastic lesion) contained transforming c-Ki-ras genes when examined by the NIH 3T3 focus assay. Hybridization of allele-specific oligonucleotides to c-Ki-ras sequences amplified by the polymerase chain reaction demonstrated the presence of a specific G-35----A-35 point mutation in codon 12 in each of the NIH 3T3 foci as well as the mammary carcinomas. This mutation resulted in the substitution of the normal glycine with an aspartic acid. Furthermore, this mutation in the c-Ki-ras proto-oncogenes was also detected in 9 of 10 hyperplastic alveolar nodules. These results demonstrate that the specific c-Ki-ras mutation is a preneoplastic event in MNU-induced mouse mammary carcinogenesis.
Mol Cell Biol 1990 Apr
PMID:Transforming c-Ki-ras mutation is a preneoplastic event in mouse mammary carcinogenesis induced in vitro by N-methyl-N-nitrosourea. 218 Dec 80


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