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Query: UNIPROT:P06889 (Mol)
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Class II MHC (Ia) molecules have been shown to be critical as restriction elements in the T helper/inducer cell recognition of antigen. Efforts to determine the role of allelic variation in MHC restricted antigen presentation have included the use of serologically selected mutants to correlate structural variations in Class II molecules with changes in the antigen presenting function of Ia bearing cells. Such studies have revealed that serologically selected mutations tend to occur in a single immunodominant region and that even a single amino acid substitution can alter T cell recognition of Ia molecules. We report here the characterization of two more serologically selected Class II A beta chain mutations. Each is due to a single base change which alters a single amino acid. One of these mutations is in the third hypervariable region (amino acid 64--glutamine to arginine) and alters the antigen presenting function. The second mutation at amino acid 48, though a relatively non-conservative change (arginine to cysteine), has no effect on APC phenotype. Such a result would be predicted based on comparisons made with the proposed three dimensional crystallographic structure of Class I molecules and models proposed for Class II molecules based on Class I structure. The amino acid change at position 48 is in a portion of the molecule that is most likely unavailable to bind antigen or interact with T cell receptor whereas the mutation at amino acid 64 is on an exposed face of the alpha helix, a region which could affect interaction with either antigen and/or the T cell receptor.
Mol Immunol 1990 Jul
PMID:Functional and molecular characterization of I-A kappa beta mutants is consistent with the predicted three dimensional structure of class II MHC molecules. 239 36

Employing the known three-dimensional (3D) structure of trypsin, we constructed simple graphics models of human-activated protein C and thrombin catalytic domains. Considering the structural analysis of bovine trypsin and pancreatic trypsin inhibitor complex, the difference of active-site amino acid sequences of human protein C inhibitor and antithrombin III and their inhibitory selectivity toward activated protein C and thrombin, we estimated the enzymatic subsites of activated protein C and thrombin and mapped them on the graphics models. Predicted favorable contacts can explain substrate selectivity of the enzymes. In this study, we used two types of modified ALPHA representations extensively. Since almost no report on the 3D structure of a blood coagulation factor has appeared and even an extensive molecular mechanics or dynamics calculation cannot produce satisfying results, simple graphics representation has several advantages.
J Mol Graph 1989 Sep
PMID:Mapping active sites of blood coagulation serine proteases--activated protein C and thrombin--on simple graphics models. 248 54

The induction of antigen-specific T cell activation is highly dependent on accessory cells (AC) which present processed antigenic fragments associated with MHC molecules and provide costimulatory signals for T cells. Antigen-specific T cell activation requires cross-linking of the TCR and the reception of one or more nonantigen-specific signals which eventually lead to T cell activation and proliferation. This sequence of events can be mimicked by lectins, bacterial enterotoxins, and anti-TCR antibodies in conjunction with APC or the combination of phorbol esters and Ca ionophores. Although the combination of PMA + Ca ionophore and certain types of T-T interactions result in APC independent T cell activation, it is generally assumed that physiologic T cell activation requires APC. The seemingly direct activation of T cells by other T cells is rather surprising in view of the known APC dependence of antigen, lectin and anti-TCR mediated T cell activation. It is conceivable that T cell mediated T cell activation is due to "cryptic" APC contamination because the total absence of APC is difficult to disprove. In reality, neither total depletion nor residual contamination with APC can be proven or disproven experimentally. Thus it can be legitimately argued that both APC dependent and independent T cell activation occur, albeit under different experimental conditions. For instance, it is possible that APC independent activation of T cells by lectins and anti-TCR antibodies would require high concentrations of activators to overide their dependence on APC. It is also conceivable and, in our opinion quite likely, that once activated, T cells could propagate T cell activation through T-T interactions. In this report we test two hypotheses: (1) The triggering of resting T cells leading to autocrine cell proliferation depends entirely on cross-linking TCR molecules, and (2) The presence of activated T cells facilitates TCR mediated activation of resting T cells without the participation of conventional APC. We present evidence that highly purified, small resting T cells can be reproducibly activated with high doses of ConA, plastic bound anti-CD3 mab and its F(ab')2 fragments. This APC independent response results in blastic transformation, expression of the IL2 Receptor, the secretion of IL2 and significant proliferation of both CD4+ and CD8+ murine T cells. These observations demonstrate that vigorous cross-linking of TCRs by anti-CD3 mab and, presumably ConA, is sufficient to induce T cell activation and autocrine (IL2 driven) proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1989
PMID:Direct activation of murine resting T cells by con A or anti-CD3 Ig. 253 86

cDNAs encoding human proteins C and S have been used to screen a panel of mouse-human somatic cell hybrids to determine the chromosomal location of their respective genes. The gene for human protein C is located on chromosome 2, whereas that for protein S is located on chromosome 3. Analysis of human genomic DNA restriction endonuclease fragmentation patterns suggests that the human protein S gene is greater than 40 kb in size and contains a minimum of 11 introns.
Somat Cell Mol Genet 1988 Jan
PMID:Genes for human vitamin K-dependent plasma proteins C and S are located on chromosomes 2 and 3, respectively. 282 67

The binding of the U1 small nuclear ribonucleoprotein (snRNP)-specific proteins C, A, and 70K to U1 small nuclear RNA (snRNA) was analyzed. Assembly of U1 snRNAs from bean and soybean and a set of mutant Xenopus U1 snRNAs into U1 snRNPs in Xenopus egg extracts was studied. The ability to bind proteins was analyzed by immunoprecipitation with monospecific antibodies and by a protein-sequestering assay. The only sequence essential for binding of the U1-specific proteins was the conserved loop sequence in the 5' hairpin of U1. Further analysis suggested that protein C binds directly to the loop and that the assembly of proteins A and 70K into the RNP requires mainly protein-protein interactions. Protein C apparently recognizes a specific RNA sequence rather than a secondary structural element in the RNA.
Mol Cell Biol 1988 Nov
PMID:Loop I of U1 small nuclear RNA is the only essential RNA sequence for binding of specific U1 small nuclear ribonucleoprotein particle proteins. 297 20

The clearance of thrombin seems to occur at more than one site and by different mechanisms. This contributes to maintaining thrombin at the right concentrations to act optimally on its various substrates, and thus, to produce the proper amount of proteolytic conversions so that coagulation is precisely controlled. The vascular endothelium plays a major role in thrombin regulation and clearance. It contains heparin-like binding sites and thrombomodulin which serve as cofactors for the thrombin-antithrombin III reaction and the activation of protein C, respectively. In addition, thrombomodulin also serves as a receptor for endothelial cell mediated thrombin endocytosis. Thrombin clearance, which occurs following reaction with antithrombin III or thrombomodulin, probably takes place at different stages in hemostasis.
Mol Cell Biochem 1986 Aug
PMID:Clearance of thrombin in vivo: significance of alternative pathways. 302 20

An Escherichia coli strain transfected with a plasmid containing four linked human proinsulin genes was grown in the presence of 35S and 3H labelled amino acids to gain access to human insulin that was radiolabelled at 19 evenly distributed sites throughout the amino acid sequence. The multi-proinsulin precursor was cleaved at methionine residues with cyanogen bromide, then the individual proinsulin units were folded via their S-cysteine sulfonate derivative and converted to insulin by enzymatic digestion. Purification steps were carried out by ion-exchange and reverse-phase HPLC techniques. The final radiolabelled biosynthetic human insulin was produced at a specific activity of up to 300 Ci/mmol, and was shown to be indistinguishable from commercially available human insulin according to HPLC behavior, amino acid analysis, immunoreactivity and biological activity. A comparison of the kinetics of processing of 35S/3H-labelled biosynthetic human insulin and 125I-labelled commercial human insulin by murine TA3 hybridoma antigen presenting cells demonstrated that radiolabelled biosynthetic insulin was processed approximately 16 times slower than its iodinated counterpart. Measurable 125I TCA soluble radioactivity was detected extracellularly within 15 min whereas the same amount of extracellular TCA soluble 3H/35S radioactivity was not seen until 240 min. These results begin to address the importance of using a biosynthetically labelled protein as opposed to an iodinated protein to study how an APC handles antigen in a physiological manner.
Mol Immunol 1988 Dec
PMID:Purification and characterization of radiolabelled biosynthetic human insulin from Escherichia coli. Kinetics of processing by antigen presenting cells. 307 Mar 57

A variety of bacterial lipopolysaccharide (LPS) preparations with highly defined primary polysaccharide chemical structure and/or aggregate macromolecular composition have been employed to examine the molecular requirements for activation of the classical and alternative pathways of human serum complement. Evidence is presented for two independent modes of polysaccharide dependent activation of the APC by LPS. One mechanism is dependent upon specific O-antigen polysaccharides and the second is defined by a specific L-glycero-D-mannoheptose/glucose region of the core oligosaccharide. LPS O-antigen polysaccharide but not core oligosaccharide determinants can convert sheep erythrocytes to cells capable of initiating the APC. The data presented provide convincing evidence that the tertiary assembly of individual LPS subunits into an aggregate macromolecule is a critical determinant in the expression of APC activity by LPS. The results of these studies provide strong evidence that CPC activation by LPS is restricted to the Re-chemotype and isolated lipid A. LPS isolated from other R-chemotypes as well as native wild type LPS preparations do not activate the CPC, in spite of the fact that the former LPS preparations contain more lipid A than polysaccharide on a percentage by wt basis. The presence of core polysaccharide L-glycero-D-mannoheptose, which provides a critical recognition role for activation of the APC, appears to negatively regulate CPC activation in a similar inverse relationship. In addition, the presence of polysaccharide containing LPS subunits in synthetic mixed LPS micellar aggregates can also restrict CPC activation by Re LPS subunits, most probably by steric hindrance at the LPS macromolecular surface. Our data are consistent with the hypothesis that activation of either pathway of human serum complement by a given LPS preparation is a mutually exclusive event dictated by the presence or absence of L-glycero-D-mannoheptose.
Mol Immunol 1987 Apr
PMID:Activation of human serum complement by bacterial lipopolysaccharides: structural requirements for antibody independent activation of the classical and alternative pathways. 330 24

The cloned bovine prothrombin gene has been characterized by partial DNA sequence analysis, including the 5' and 3' flanking sequences and all the intron-exon junctions. The gene is approximately 15.4 x 10(3) base-pairs in length and comprises 14 exons interrupted by 13 introns. The exons coding for the prepro-leader peptide and the gamma-carboxyglutamic acid-containing region are similar in organization to the corresponding exons in the factor IX and protein C genes. This region has probably evolved as a result of recent gene duplication and exon shuffling events. The exons coding for the kringles and the serine protease region of the prothrombin gene are different in organization from the homologous regions in other genes, suggesting that introns have been inserted into these regions after the initial gene duplication events.
J Mol Biol 1988 Mar 05
PMID:Structure and evolution of the bovine prothrombin gene. 337 42

The T cell surface molecules Lyt-2 and L3T4 are strongly correlated with the class of MHC gene product recognized by the T cell bearing them. The L3T4 molecule has been proposed to play a role in enhancing recognition of antigen:Ia by specific T cells. In the present experiments, we have explored the role of L3T4 in T cell activation by examining the effects of the L3T4-specific monoclonal antibody GK1.5 on T cell responses in the presence or absence of class II-MHC gene products. Our studies show that GK1.5 inhibits T cell activation in the absence of class II-MHC gene products, while antibodies to other T cell surface molecules do not transduce negative signals to the same cells. We interpret our results as suggesting a signaling role for L3T4 and, by inference, for Lyt-2 as well. We would propose that L3T4 molecules on the class II-restricted T cell initiate the interaction between the L3T4+ T cell and its class II-MHC gene product bearing target cell (B cell, APC). This initial contact is important in allowing a finite time for antigen, Ia, and the T cell receptor to form an activating complex, which in turn transduces a dominant on signal to the cell. In the absence of specific antigen, or if the class II-bearing cell is of the wrong MHC genotype, so that the antigen:Ia receptor is not aggregated, then the association of L3T4 with class II molecules transduces a net negative signal to the T cell. We suggest that this negative signal is responsible for T cell:target cell deconjugation under these circumstances. Thus, we would propose that L3T4 initiates T cell:Ia-bearing cell interactions and, a finite time later, signals the T cell to discontinue the interaction unless a stimulating level of the antigen:Ia complexes for which the T cell's receptor is specific is present.
J Mol Cell Immunol 1986
PMID:The role of L3T4 in T cell activation: L3T4 may be both an Ia-binding protein and a receptor that transduces a negative signal. 350 16


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