Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Region II of the malaria circumsporozoite (CS) protein is highly conserved between the CS proteins of different species of malaria. Amino acid sequences homologous to that of region II are found in thrombospondin, properdin, von Willebrand factor and a few other proteins. We show here that the native CS protein from the rodent parasite Plasmodium berghei, and recombinant Plasmodium vivax and Plasmodium falciparum CS proteins containing region II, but not recombinant proteins lacking region II, specifically bind to sulfatides and cholesterol-3-sulfate. The binding is abolished following reduction and alkylation of the proteins. Region II contains 2 cysteines separated by only 3 amino acids, S(N), V, T, and these are the only cysteines present in our recombinant proteins. Therefore, our findings strongly suggest that the region II cysteines are linked by a disulfide bond forming a small peptide loop. We also present evidence that the recognition of sulfatides, cholesterol-3-sulfate, or other cross-reactive sulfated macromolecules by region II may be required during sporozoite invasion of liver cells. Antibodies to a peptide representing region II react with live sporozoites and with sporozoites fixed with glutaraldehyde, indicating that this region is exposed on the surface of the parasites. Furthermore, we have found that the sulfatide and cholesterol-3-sulfate recognition by the CS proteins, and the invasion of hepatocytes by P. berghei sporozoites, are specifically inhibited by dextran sulfate.
Mol Biochem Parasitol 1992 Aug
PMID:Binding of malarial circumsporozoite protein to sulfatides [Gal(3-SO4)beta 1-Cer] and cholesterol-3-sulfate and its dependence on disulfide bond formation between cysteines in region II. 151 21

The human fur gene encodes a protein, designated furin, the C-terminal half of which contains a transmembrane and a cysteine-rich receptor-like domain. The N-terminal half of furin exhibits striking primary amino acid sequence similarity to the catalytic domains of members of the subtilisin family of serine proteases. We here report characteristics of the furin protein and propose a three-dimensional model for its presumptive catalytic domain with characteristics, that predict furin to exhibit an endoproteolytic cleavage selectivity at paired basic residues. This prediction is substantiated by transfection and cotransfection experiments, using COS-1 cells. Full length fur cDNA evokes the specific synthesis of two polypeptides of about 100 kDa and 90 kDa as appeared from Western blot analysis of transfected COS-1 cells using a polyclonal anti-furin antiserum. Functional analysis of furin was performed by cotransfection of fur cDNA with cDNA encoding the 'wild type' precursor of von Willebrand factor (pro-vWF) and revealed an increased proteolytic processing of provWF. In contrast, cotransfection of fur cDNA with a recombinant derivative (provWFgly763), having the arginine residue adjacent to the proteolytic cleavage site (arg-ser-lys-arg) replaced by glycine, revealed that provWFgly763 is not processed by the fur gene product. We conclude that in higher eukaryotes, furin is the prototype of a subtilisin-like class of proprotein processing enzymes with substrate specificity for paired basic residues.
Mol Biol Rep 1990 Nov
PMID:Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. 209 3

Agglutination of human platelets by bovine von Willebrand factor (vWF) or by human vWF in the presence of ristocetin is inhibited by ADP and by several other platelet agonists but not by epinephrine. Vincristine, which causes a shape change by disrupting microtubules, neither inhibited agglutination nor blocked the effect of ADP. The action of ADP was blocked by ATP, by p-fluorosulfonylbenzoyladenosine, and by the thiol-reactive regents cytochalasin A and p-chloromercuribenzenesulfonate. In contrast to its effects on vWF, ADP enhanced agglutination induced by wheat germ lectin. ADP caused a small decrease in the number and affinity of binding sites for vWF on platelets, too small to explain the inhibition of agglutination. The ability of ADP and other agonists to inhibit agglutination appears to be related neither to inhibition of adenylate cyclase nor to the loss of their discoid shape but rather to the membrane changes that accompany the shape change.
Mol Pharmacol 1990 Feb
PMID:Effect of platelet activation on the agglutination of platelets by von Willebrand factor. 215 74

In plasma, antihemophilic factor (factor VIII) exists as a 200-kilodalton heavy-chain polypeptide in a metal ion association with an 80-kilodalton light-chain polypeptide. This complex is bound by hydrophobic and hydrophilic interactions to a large multimeric glycoprotein, von Willebrand factor (vWF). Accumulation of secreted human factor VIII activity expressed in Chinese hamster ovary cells requires the addition of serum in the growth medium, which provides vWF. Here we report that coexpression of vWF with factor VIII in Chinese hamster ovary cells resulted in increased stable accumulation of factor VIII activity in the absence of serum in the growth medium. In the coexpressing cells, the vWF cDNA transcription unit was transcribed to yield mRNA which was efficiently translated. vWF was properly processed and secreted to yield disulfide-bonded high-molecular-weight multimers similar to those observed in vWF secreted from human endothelial cells. Nuclear run-on assays showed that the factor VIII gene was transcribed at a level similar to that of the vWF gene, but the mRNA did not accumulate to high levels in the cytoplasm. In addition, although the translation efficiency of the factor VIII mRNA was similar to that of vWF, the processing and secretion of the factor VIII primary translation product was dramatically reduced compared with vWF. These results demonstrate that in Chinese hamster ovary cells both factor VIII mRNA accumulation and the processing and secretion of the primary factor VIII translation product are inefficient processes.
Mol Cell Biol 1989 Mar
PMID:Effect of von Willebrand factor coexpression on the synthesis and secretion of factor VIII in Chinese hamster ovary cells. 249 45

The receptor on human neutrophils (polymorphonuclear leukocytes) that mediates cellular adherence consists of two noncovalently associated subunits, designated alpha M (Mac-1 alpha, Mol alpha, or CD11b; Mr, 170,000) and beta (Mac-1 beta, Mol beta, or CD18; Mr, 100,000). We isolated a cDNA clone for the human neutrophil alpha M subunit by screening a lambda gt 11 cDNA library made from chronic myelogenous leukemia neutrophils by using an affinity-purified rabbit polyclonal antibody directed against the alpha M subunit. We used this cDNA clone to obtain additional clones from cDNA libraries made from differentiated HL-60 promyelocytic leukemia cells. Together these cDNAs constitute the complete 1137-amino acid sequence for the mature human alpha M subunit protein. The deduced amino acid sequence indicates the presence of an extensive extracellular domain with three putative metal-binding regions, (i) an amino acid region that is homologous to the A domain of von Willebrand factor, (ii) a 26-amino acid hydrophobic sequence that is a potential transmembrane domain, and (iii) a 19-amino acid cytoplasmic region. The amino acid sequence for the human neutrophil alpha M subunit contains regions that are closely related to amino acid sequences of adhesion receptors belonging to the integrin family.
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PMID:cDNA sequence for the alpha M subunit of the human neutrophil adherence receptor indicates homology to integrin alpha subunits. 256 62

Many of the proteins that mediate cell adhesion processes processes-fibronectin, fibrinogen, vitronectin, von Willebrand factor, osteopontin, laminin and various collagens--contain the amino acid sequence Arg-Gly-Asp. Short peptides that include this sequence have been shown to inhibit the interactions of cell adhesion proteins with their receptors and to have dramatic effects on developmental processes involving cellular recognition. In order to determine which conformations are accessible to Arg-Gly-Asp containing peptides, we analyzed tri-, tetra- and pentapeptides using molecular mechanics and Monte Carlo methods, and studied the solution conformations of the pentapeptide Gly-Arg-Gly-Asp-Ser using nuclear magnetic resonance techniques. The Monte Carlo method was used to: (a) identify the low energy conformations of the peptides and (b) evaluate their thermodynamic properties. In the case of the pentapeptide Gly-Arg-Gly-Asp-Gly, the four stable conformations include three with reverse turns and one open structure. The conformations found in this analysis are compatible with the nuclear magnetic resonance (nuclear Overhauser effect) data.
J Mol Recognit 1989 Dec
PMID:Recognition in cell adhesion. A comparative study of the conformations of RGD-containing peptides by Monte Carlo and NMR methods. 263 44

To study the roles played by cardiac valvular endothelium in normal and pathologic conditions, we have established and characterized a system of bovine valvular endothelial cells (VEC) in culture. Viable VEC from calf atrioventricular valves were obtained by a non-enzymatic procedure using 3 mM ethylenediamine-tetraacetic acid (EDTA) as dissociating agent. The cells grown in Dulbecco's modified Eagle's medium supplemented with non-essential amino acids, vitamins and 20% fetal calf serum, developed as monolayers of closely apposed polygonal cells which were subcultured for up to seven passages. VEC maintained in culture the general ultrastructure displayed in vivo, expressed von Willebrand factor, presented angiotensin converting enzyme activity and synthesized a rich extracellular matrix. VEC preserved the cell surface anionic sites (detected with cationized ferritin, pI 8.4) and cationic sites (visualized with haemeundecapeptide pI 4.85), and took up, especially by adsorptive endocytosis, albumin-gold conjugate. The cells were coupled by functional communicating (gap) junctions, as demonstrated by microinjection of 6-carboxyfluorescein. VEC in culture produced fibronectin, prostacyclin, hyaluronic acid and heparin-like glycosaminoglycans (identified by electrophoresis, enzyme digestion, and deaminative cleavage of molecules). These properties render cultured VEC a suitable model for investigating their functions and involvement in normal and pathologic heart valves.
J Mol Cell Cardiol 1988 Feb
PMID:Calf cardiac valvular endothelial cells in culture: production of glycosaminoglycans, prostacyclin and fibronectin. 284 May 11

In order to facilitate investigation of the cells responsible for overproduction of type VI collagen in the extracellular matrix surrounding the capillaries of diabetic rat myocardium, procedures have been developed for the isolation from this tissue of endothelial cells as well as a cell type identified as pericytes. This was accomplished by enzymatic and mechanical disruption of ventricles from young rats (125 g) followed by removal of myocytes through their nonadherence to tissue culture surfaces. Endothelial cells were separated by fluorescence-activated cell sorting after staining with rhodamine-labeled acetylated low density lipoprotein and were identified by their monolayer growth pattern, reaction with anti-von Willebrand factor and the ability to form capillary-like tubes induced by low serum concentration. Pericytes were purified by selective scraping for removal of other cell types and were identified by their irregular shape, overlapping growth pattern at confluence, reaction with anti-smooth muscle actin and content of GLUT4 glucose transporter. Fibroblasts, visualized after staining with rhodamine-labeled alpha 2-macroglobulin, were only rarely detected. Analysis of collagen by immunoblotting indicated formation by both cell types of alpha 1(IV) collagen as well as the three subunits of type VI (alpha 3 at 205 kDa and alpha 1 plus alpha 2 at 150 kDa). Both endothelial cells and pericytes demonstrated transcripts for types VI, IV and I collagen, as well as fibronectin, but while the level of the mRNA for type IV collagen was higher in pericytes than in endothelial cells, the reverse was true for collagens VI and I and fibronectin. These observations suggest that both endothelial cells and pericytes contribute to formation of the myocardial capillary matrix, but that changes involving only type VI collagen, such as occur in diabetic cardiomyopathy, may reflect a response primarily of endothelial cells.
J Mol Cell Cardiol 1995 May
PMID:Isolation of rat heart endothelial cells and pericytes: evaluation of their role in the formation of extracellular matrix components. 747 75

In both tissue sections and cell culture, the endothelial nature of a cell is most commonly determined by demonstration of its expression of von Willebrand factor (vWf) protein and/or mRNA. Thus, the mechanism of cell-type-specific transcriptional regulation of the vWf gene is central to studying the basis of endothelial-cell-specific gene expression. In this study, deletion analyses were carried out to identify the region of the vWf gene which regulates its endothelial-cell-specific expression. A 734-bp fragment which spans the sequence from -487 to +247 relative to the transcription start site was identified as the cell-type-specific promoter. It consists of a minimal core promoter located between -90 and +22, a strong negative regulatory element located upstream of the core promoter (ca. -500 to -300), and a positive regulatory region located downstream of the core promoter in the first exon. The activity of the core promoter is not cell type specific, and the negative regulatory region is required to inhibit its activity in all cell types. The positive regulatory region relieves this inhibition only in endothelial cells and results in endothelial-cell-specific gene expression. The positive regulatory region contains sequences predicting possible SP1, GATA, and octamer binding sites. Mutations in either the SP1 or octamer sequence have no effect on transcriptional activity, while mutation in the GATA binding element totally abolishes the promoter activity. Evidence that a GATA factor is involved in this interaction is presented. Thus, the positive regulatory region with an intact GATA binding site is required to overcome the inhibitory effect of the negative regulatory element and activate vWf gene expression in an endothelial-cell-specific manner.
Mol Cell Biol 1994 Feb
PMID:Endothelial-cell-specific regulation of von Willebrand factor gene expression. 750 10

Unstimulated endothelial cell (EC) cultures express low levels of intercellular adhesion molecule-1 (ICAM-1) and their expression can be enhanced by inflammatory cytokines such as tumor necrosis factor alpha (TNF). Three monoclonal antibodies (MoAbs) highly reactive with TNF-stimulated human ECs were established and defined to recognize a 95 kDa cell surface protein specifically expressed on cytokine-activated ECs, which was immunochemically identified as ICAM-1. The quantitative immunoassay of soluble and insoluble ICAM-1 could be performed with two different MoAbs. Secretion of fibronectin or the von Willebrand factor, was not significantly enhanced with TNF stimulation. Cellular expression of ICAM-1 was drastically induced by TNF or interleukin-1 stimulation, and the moderate expression with delayed-action was observed only by lipopolysaccharide stimulation. A maximal amount of soluble ICAM-1 was released from ECs stimulated only by TNF, apparently in a dose dependent manner, but no significant release of ICAM-1 was induced by thrombin interleukin-2, or lipopolysaccharides. Released levels of soluble ICAM-1 from interleukin-1-stimulated ECs were apparently diminished as compared with those from TNF-stimulated cells. These results suggest that release of soluble ICAM-1 from EC surfaces can be most significantly enhanced by TNF-specific signaling, and prospectively, should be a sensitive indicator of intravascular inflammation in acute endothelium injury.
Mol Cell Biochem 1994 Oct 26
PMID:Immunoenzymometric analysis for expression and shedding of intercellular adhesion molecule-1 on human endothelial cells stimulated with cytokines or lipopolysaccharide. 753 74


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