Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In previous papers we provided evidence for a glucocorticoid (GC) responsive site in a highly purified rat liver plasma membrane (PM) fraction, which has proved to be osmotically active, 'right side-out' vesicles, free of CBG, glucocorticoid receptors (GR) and ATP (J. Steroid Biochem. Molec. Biol. 42 (1992) 737-756 and 757-771). This site, now called 'GC importer', mediates active transmembrane transport of corticosterone (B). Pronounced specificity, including stereo- and enantiomeric specificity, of ligand-GC importer interaction was demonstrated by competition assays using 54 different steroidal hormones and molecules. Important structural prerequisites for ligands with high specificity for the GC importer are plane C21-steroid hormones with 1-ene and/or 4-ene or 5alpha-reduced configuration, and/or OH-group(s) at C11beta>C17alpha>C21. Unexpectedly, other preferred ligands are C17alpha-ethynyl steroids like estrogens with an OH- or OCH3-group at C3 (EE2, mestranol) as well as progestins with C3-OH and 4-ene configuration (ethynodiol). C21-steroids with 11alpha-OH, 11-keto, 16alpha-CH3, 16beta-CH3, 16alpha-OH or 5beta-reduced configuration are low specificity ligands. The importer even displays different specificity for enantiomers (levonorgestrel>L-norgestrel). Altogether, the GC importer preferentially recognizes active GC and natural progestins which act as GC-antagonist (e.g. prednisolone>11beta-cortisol = B > or = progestins). Synthetic GC-agonists (e.g. dexamethasone, betamethasone, triamcinolone), most synthetic progestins, biologically inactive GC (e.g. 11alpha-cortisol, prednisone, cortisone, 11-dehydro-B), mineralocorticoids (aldosterone), natural estrogens (e.g. E1, E2, E3), DES and vitamin D3 derivatives do not interact with the GC importer. Osmotic shrinkage experiments revealed that interaction of high as well as low specificity ligands with the GC importer comprises reversible binding and transport through the PM. The ligand specificity profile of the GC importer and the GR exhibit pronounced differences, suggesting that both GC recognizing sites are different proteins. Performing immunoblotting, using specific mono- and polyclonal antibodies directed against the intracellular rat GR, of the PM pretreated with the membrane protein solubilizing detergent CHAPSO, we found that specific steroid binding to the PM site is not due to contamination with GR. Colchicine, daunorubicine, quinine, reserpine, verapamil and vinblastine, representatives of lipophilic xenobiotics which are known to be transported out of cells by the glycoprotein P170, did not compete with B for uptake into PM-vesicles, indicating that the GC importer is not a member of the ABC/mdr superfamily. The GC importer seems to be an additional link in the chain of steroid signal transduction and may be functionally involved in the action of natural GC-agonists and GC-antagonists.
J Steroid Biochem Mol Biol 1998 Jan
PMID:Glucocorticoid-recognizing and -effector sites in rat liver plasma membrane. Kinetics of corticosterone uptake by isolated membrane vesicles. III. Specificity and stereospecificity. 956 12

The gene devA of the filamentous heterocyst-form-ing cyanobacterium Anabaena sp. strain PCC 7120 encodes a protein with high similarity to ATP-binding cassettes of ABC transporters. Mutant M7 defective in the devA gene is arrested in the development of heterocysts at an early stage and is not able to fix N2 under aerobic conditions. The devA gene is differentially expressed in heterocysts. To gain a better understanding of the structural components of this putative ABC transporter, we determined the complete nucleotide sequence of the entire gene cluster. The two additional genes, named devB and devC, encode proteins with similarities to membrane fusion proteins (DevB) of several ABC exporters and to membrane-spanning proteins (DevC) of ABC transporters in general. Site-directed mutations in each of the three genes resulted in identical phenotypes. Heterocyst-specific glycolipids forming the laminated layer of the envelope were identified in lipid extracts of M7 and in the site-directed mutants. However, transmission electron microscopy revealed unequivocally that the glycolipid layer is missing in mutant M7. Ultrastructural analysis also confirmed a developmental block at an early stage of differentiation. The results of this study suggest that the devBCA operon encodes an exporter of glycolipids or of an enzyme that is necessary for the formation of the laminated layer. The hypothesis is proposed that an intact envelope could be required for further heterocyst differentiation.
Mol Microbiol 1998 Mar
PMID:The DevBCA exporter is essential for envelope formation in heterocysts of the cyanobacterium Anabaena sp. strain PCC 7120. 957 Apr 4

The Escherichia coli msbA gene, first identified as a multicopy suppressor of htrB mutations, has been proposed to transport nascent core-lipid A molecules across the inner membrane (Polissi, A., and Georgopoulos, C. (1996) Mol. Microbiol. 20, 1221-1233). msbA is an essential E. coli gene with high sequence similarity to mammalian Mdr proteins and certain types of bacterial ABC transporters. htrB is required for growth above 32 degreesC and encodes the lauroyltransferase that acts after Kdo addition during lipid A biosynthesis (Clementz, T., Bednarski, J., and Raetz, C. R. H. (1996) J. Biol. Chem. 271, 12095-12102). By using a quantitative new 32Pi labeling technique, we demonstrate that hexa-acylated species of lipid A predominate in the outer membranes of wild type E. coli labeled for several generations at 42 degreesC. In contrast, in htrB mutants shifted to 42 degreesC for 3 h, tetra-acylated lipid A species and glycerophospholipids accumulate in the inner membrane. Extra copies of the cloned msbA gene restore the ability of htrB mutants to grow at 42 degreesC, but they do not increase the extent of lipid A acylation. However, a significant fraction of the tetra-acylated lipid A species that accumulate in htrB mutants are transported to the outer membrane in the presence of extra copies of msbA. E. coli strains in which msbA synthesis is selectively shut off at 42 degreesC accumulate hexa-acylated lipid A and glycerophospholipids in their inner membranes. Our results support the view that MsbA plays a role in lipid A and possibly glycerophospholipid transport. The tetra-acylated lipid A precursors that accumulate in htrB mutants may not be transported as efficiently by MsbA as are penta- or hexa-acylated lipid A species.
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PMID:Function of Escherichia coli MsbA, an essential ABC family transporter, in lipid A and phospholipid biosynthesis. 957 4

Vibrio cholerae, the bacterium that causes cholera, has a pathogenic cycle consisting of a free-swimming phase outside its host, and a sessile virulent phase when colonizing the human small intestine. We have cloned the V. cholerae homologue of the rpoN gene (encoding sigma54) and determined its role in the cholera pathogenic cycle by constructing an rpoN null mutant. The V. cholerae rpoN mutant is non-motile; examination of this mutant by electron microscopy revealed that it lacks a flagellum. In addition to flagellar synthesis, sigma54 is involved in glutamine synthetase expression. Moreover, the rpoN mutant is defective for colonization in an infant mouse model of cholera. We present evidence that the colonization defect is distinct from the non-motile and Gln phenotypes of the rpoN mutant, implicating multiple and distinct roles of sigma54 during the V. cholerae pathogenic cycle. RNA polymerase containing sigma54 (sigma54-holoenzyme) has an absolute requirement for an activator protein to initiate transcription. We have identified three regulatory genes, flrABC (flagellar regulatory proteins ABC) that are additionally required for flagellar synthesis. The flrA and flrC gene products are sigma54-activators and form a flagellar transcription cascade. flrA and flrC mutants are also defective for colonization; this phenotype is probably independent of non-motility. An flrC constitutive mutation (M114-->I) was isolated that is independent of its cognate kinase FlrB. Expression of the constitutive FlrCM114-->I from the cholera toxin promoter resulted in a change in cell morphology, implicating involvement of FlrC in cell division. Thus, sigma54 holoenzyme, FlrA and FlrC transcribe genes for flagellar synthesis and possibly cell division during the free-swimming phase of the V. cholerae life cycle, and some as yet unidentified gene(s) that aid colonization within the host.
Mol Microbiol 1998 May
PMID:Distinct roles of an alternative sigma factor during both free-swimming and colonizing phases of the Vibrio cholerae pathogenic cycle. 963 54

Rhizobium tropici nodulates and fixes nitrogen in bean. In the R. tropici strain CFN299 we identified and characterized teu genes (tropici exudate uptake) induced by bean root exudates, localized by insertion of a promoter-less Tn5-gusA1 transposon. teu genes are present on a plasmid of around 185 kb that is conserved in all R. tropici strains. Proteins encoded by teu genes show similarity to ABC transporters, specifically to ribose transport proteins. No induction of the teu genes was obtained by treatment with root exudates from any of several other plants tested, with the exception of Macroptilium atropurpureum, which is also a host plant for R. tropici. It appears that the inducing compound is characteristic of bean and closely related legumes. It is present in root exudates, but not in seeds. This compound is removed, presumably by metabolism, from the exudates by the majority of bean-nodulating rhizobia (such as R. etli, R. leguminosarum bv. phaseoli and R. giardinii). The principal inducing compound has not been identified, but some induction was obtained using trigonelline. The CFN299 strain seems to have an additional uptake system, as no phenotype is observed in two different mutants. R. tropici strain CIAT899, on the other hand, must have only one uptake system, since a mutant bearing an insertion in the teu genes could not remove the compound from the exudates as efficiently as the wild type, and it showed diminished nodulation competitiveness.
Mol Gen Genet 1998 Jun
PMID:Rhizobium tropici teu genes involved in specific uptake of Phaseolus vulgaris bean-exudate compounds. 967 Oct 27

A cyclic AMP (cAMP)-inducible enhancer in the pig urokinase-type plasminogen activator gene located 3.4 kb upstream of the transcription initiation site is composed of three protein-binding domains, A, B, and C. Domains A and B each contain a CRE (cAMP response element)-like sequence but require the adjoining C domain for full cAMP responsiveness. A tissue-specific transcription factor, LFB3/HNF1beta/vHNF1, binds to the C domain. Mutation analyses suggest that the imperfect CRE and LFB3-binding sequences are required for tight coupling of hormonal and tissue-specific regulation. CREB and ATF1 bind to domains A and B, and this binding is enhanced upon phosphorylation by cAMP-dependent protein kinase (protein kinase A [PKA]). Analysis in a mammalian two-hybrid system revealed that CREB/ATF1 and LFB3 interact and that transactivation potential is enhanced by PKA activation. Interestingly, however, phosphorylation of CREB at Ser-133 does not contribute to its interaction with LFB3. The region of LFB3 involved in its interaction with CREB/ATF1 lies, at least partly, between amino acids 400 and 450. Deletion of this region removed the ability of LFB3 to mediate cAMP induction of the ABC enhancer but did not impair its basal transactivation activity on the albumin promoter. Thus, the two activities are distinct functions of LFB3.
Mol Cell Biol 1998 Aug
PMID:Role of tissue-specific transcription factor LFB3 in a cyclic AMP-responsive enhancer of the urokinase-type plasminogen activator gene in LLC-PK1 cells. 967 80

Downregulation of the major autolysin in Streptococcus pneumoniae leads to penicillin tolerance, a feature that is characterized by the ability to survive but not grow in the presence of antibiotic. Screening a library of mutants in pneumococcal surface proteins for the ability to survive 10x minimum inhibitory concentration (MIC) of penicillin revealed over 10 candidate tolerance genes. One such mutant contained an insertion in the known gene psaA, which is part of the psa locus. This locus encodes an ABC-type Mn permease complex. Sequence analysis of adjacent DNA extended the known genetic organization of the locus to include two new open reading frames (ORFs), psaB, which encodes an ATP-binding protein, and psaC, which encodes a hydrophobic transmembrane protein. Mutagenesis of psaB, psaC, psaA and downstream psaD resulted in penicillin tolerance. Defective adhesion and reduced transformation efficiency, as reported previously for a psaA- mutant, were phenotypes shared by psaB-, psaC- and psaD- knockout mutants. Western blot analysis demonstrated that the set of mutants expressed RecA, but none of them showed translation of the autolysin gene, which is located downstream of recA. The addition of manganese (Mn) failed to correct the abnormal physiology. These results suggest that this ABC-type Mn permease complex has a pleiotropic effect on pneumococcal physiology including adherence and autolysis. These are the first genes suggested as being involved in triggering autolysin. The results raise the possibility that loss of function of PsaA, by vaccine-induced antibody for instance, may promote penicillin tolerance.
Mol Microbiol 1998 Sep
PMID:Penicillin tolerance genes of Streptococcus pneumoniae: the ABC-type manganese permease complex Psa. 1036 Dec 89

We have designed a new cell surface expression plasmid to study the structural and membrane-topological requirements for functioning of different isoforms of CD45, a leucocyte specific member of the protein tyrosine phosphatase (PTPase) family of proteins. Use of this vector in cell transfection experiments enabled us to produce multiple CD45 isoforms (ABC, B, Null), with their extracellular segment intact, and the entire membrane spanning and intracellular C-terminal domain replaced by a GPI-membrane-anchor and VSV-tag. Our strategy facilitated the identification and analysis of chimeric proteins and selection of cell clones from low transfection efficiency experiments. We demonstrate here that simple expression of GPI-anchored CD45 isoforms on transfected Cos-1 cells does not facilitate binding to CD22+ lymphoid cells. This suggests that not only the mere presence of CD45 extracellular domains but also their assembly into higher order structures at the cell surface, is necessary in order to engage in the recognition and/or signalling processes normally used by B- and T-cells.
Mol Biol Rep 1998 Nov
PMID:Cell surface GPI-anchoring of CD45 isoforms. 987 Jun 8

Escherichia coli O8:K40 coexpresses two distinct lipopolysaccharide (LPS) structures on its surface. The O8 polysaccharide is a mannose homopolymer with a trisaccharide repeat unit and is synthesized by an ABC-2 transport-dependent pathway. The K40LPS backbone structure is composed of a trisaccharide repeating unit of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) and has an uncommon substitution, an L-serine moiety attached to glucuronic acid. The gene cluster responsible for synthesis of the K40 polysaccharide has previously been cloned and sequenced and was found to contain six open reading frames (ORFs) (P. A. Amor and C. Whitfield, Mol. Microbiol. 26:145-161, 1997). Here, we demonstrate that insertional inactivation of orf1 results in the accumulation of a semirough (SR)-K40LPS form which retains reactivity with specific polyclonal serum in Western immunoblots. Structural and compositional analysis of the SR-K40LPS reveals that it comprises a single K40 repeat unit attached to lipid A core. The lack of polymerization of the K40 polysaccharide indicates that orf1 encodes the K40 polymerase (Wzy) and that assembly of the K40 polysaccharide occurs via a Wzy-dependent pathway (in contrast to that of the O8 polysaccharide). Inactivation of orf3 also results in the accumulation of an SR-LPS form which fails to react with specific polyclonal K40 serum in Western immunoblots. Methylation linkage analysis and fast atom bombardment-mass spectrometry of this SR-LPS reveals that the biological repeat unit of the K40 polysaccharide is GlcNAc-GlcA-GlcNAc. Additionally, this structure lacks the L-serine substitution of GlcA. These results show that (i) orf3 encodes the enzyme responsible for the addition of the L-serine residue to the K40 backbone and (ii) substitution of individual K40 repeats with L-serine is essential for their recognition and polymerization into the K40 polysaccharide by Wzy.
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PMID:Assembly of the K40 antigen in Escherichia coli: identification of a novel enzyme responsible for addition of L-serine residues to the glycan backbone and its requirement for K40 polymerization. 992 39

The Bacillus subtilis sigW gene encodes an extracytoplasmic function (ECF) sigma factor that is expressed in early stationary phase from a sigW-dependent autoregulatory promoter, PW. Using a consensus-based search procedure, we have identified 15 operons preceded by promoters similar in sequence to PW. At least 14 of these promoters are dependent on sigma W both in vivo and in vitro as judged by lacZ reporter fusions, run-off transcription assays and nucleotide resolution start site mapping. We conclude that sigma W controls a regulon of more than 30 genes, many of which encode membrane proteins of unknown function. The sigma W regulon includes a penicillin binding protein (PBP4*) and a co-transcribed amino acid racemase (RacX), homologues of signal peptide peptidase (YteI), flotillin (YuaG), ABC transporters (YknXYZ), non-haem bromoperoxidase (YdjP), epoxide hydrolase (YfhM) and three small peptides with structural similarities to bacteriocin precursor polypeptides. We suggest that sigma W activates a large stationary-phase regulon that functions in detoxification, production of anti-microbial compounds or both.
Mol Microbiol 1999 Jan
PMID:Identification of target promoters for the Bacillus subtilis extracytoplasmic function sigma factor, sigma W. 998 36


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