UNIPROT:O95477 - FACTA Search

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Query: UNIPROT:O95477 (membrane-bound)
29,236 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein C (PC) anticoagulant system provides specific and efficient control of blood coagulation. The system comprises circulating or membrane-bound protein components that take part in complicated multimolecular protein complexes being assembled on specific cellular phospholipid membranes. Each of the participating proteins is composed of multiple domains, many of which are known at the level of their three-dimensional structures. The key component of the PC system, the vitamin K-dependent PC, circulates in blood as zymogen to an anticoagulant serine protease. Activation is achieved on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial PC receptor binds the Gla domain of PC and stimulates the activation. Activated PC (APC) modulates the activity of blood coagulation by specific proteolytic cleavages of a limited number of peptide bonds in factor (F)VIIIa and FVa, cofactors in the activation of FX and prothrombin, respectively. These reactions occur on the surface of negatively charged phospholipid membranes and are stimulated by the vitamin K-dependent protein S. Regulation of FVIIIa activity by APC is stimulated not only by protein S but also by FV, which, like thrombin, is a Janus-faced protein with both pro- and anticoagulant potential. However, whereas the properties of thrombin are modulated by protein-protein interactions, the specificity of FV function is governed by proteolysis by pro- or anti-coagulant enzymes. The molecular recognition of the PC system is beginning to be unravelled and provides insights into a fascinating and intricate molecular scenario.
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PMID:Molecular recognition in the protein C anticoagulant pathway. 1287 Dec 88

One mechanism whereby B cells contribute to type 1 diabetes in nonobese diabetic (NOD) mice is as a subset of APCs that preferentially presents MHC class II-bound pancreatic beta cell Ags to autoreactive CD4 T cells. This results from their ability to use cell surface Ig to specifically capture beta cell Ags. Hence, we postulated a diabetogenic role for defects in the tolerance mechanisms normally blocking the maturation and/or activation of B cells expressing autoreactive Ig receptors. We compared B cell tolerance mechanisms in NOD mice with nonautoimmune strains by using the IgHEL and Ig3-83 transgenic systems, in which the majority of B cells recognize one defined Ag. NOD- and nonautoimmune-prone mice did not differ in ability to delete or receptor edit B cells recognizing membrane-bound self Ags. However, in contrast to the nonautoimmune-prone background, B cells recognizing soluble self Ags in NOD mice did not undergo partial deletion and were also not efficiently anergized. The defective induction of B cell tolerance to soluble autoantigens is most likely responsible for the generation of diabetogenic APC in NOD mice.
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PMID:B cell selection defects underlie the development of diabetogenic APCs in nonobese diabetic mice. 1506 92

B cells play an important role in rheumatoid arthritis, but whether they are required as autoantibody-producing cells as well as APCs has not been determined. We assessed B cell autoantibody and APC functions in a murine model of autoimmune arthritis, proteoglycan (PG)-induced arthritis, using both B cell-deficient mice and Ig-deficient mice (mIgM) mice that express an H chain transgene encoding for membrane-bound, but not secreted, IgM. The IgH transgene, when paired with endogenous lambda L chain, recognizes the hapten 4-hydroxy-3-nitro-phenyl acetyl and is expressed on 1-4% of B cells. B cell-deficient and mIgM mice do not develop arthritis after immunization with PG. In adoptive transfer of PG-induced arthritis into SCID mice, T cells from mIgM mice immunized with PG were unable to transfer disease even when B cells from PG-immunized wild-type mice were provided, suggesting that the T cells were not adequately primed and that Ag-specific B cells may be required. In fact, when PG was directly targeted to the B cell Ig receptor through a conjugate of 4-hydroxy-3-nitrophenyl acetyl-PG, T cells in mIgM mice were activated and competent to transfer arthritis. Such T cells caused mild arthritis in the absence of autoantibody, demonstrating a direct pathogenic role for T cells activated by Ag-specific B cells. Transfer of arthritic serum alone induced only mild and transient arthritis. However, both autoreactive T cells and autoantibody are required to cause severe arthritis, indicating that both B cell-mediated effector pathways contribute synergistically to autoimmune disease.
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PMID:Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis. 1574 19

The protein C system provides important control of blood coagulation by regulating the activities of factor VIIIa (FVIIIa) and factor Va (FVa), cofactors in the activation of factor X and prothrombin, respectively. The system comprises membrane-bound and circulating proteins that assemble into multi-molecular complexes on cell surfaces. Vitamin K-dependent protein C, the key component of the system, circulates in blood as zymogen to an anticoagulant serine protease. It is efficiently activated on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial protein C receptor (EPCR) further stimulates the protein C activation. Activated protein C (APC) together with its cofactor protein S inhibits coagulation by degrading FVIIIa and FVa on the surface of negatively charged phospholipid membranes. Efficient FVIIIa degradation by APC requires not only protein S but also intact FV, which like thrombin is a Janus-faced protein with both procoagulant and anticoagulant potential. In addition to its anticoagulant properties, APC has antiinflammatory and antiapoptotic functions, which are exerted when APC binds to EPCR and proteolytic cleaves protease-activated receptor 1 (PAR-1). The protein C system is physiologically important, and genetic defects affecting the system are the most common risk factors of venous thrombosis. The proteins of the protein C system are composed of multiple domains and the 3-dimensional structures of several of the proteins are known. The molecular recognition of the protein C system is progressively being unraveled, giving us new insights into this fascinating and intricate molecular scenario at the atomic level.
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PMID:Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. 1586 Jul 36

Endothelial cell membrane-bound thrombomodulin (TM) plays a critical role as a cofactor in the protein C pathway, important in regulating coagulation as well as inflammation. Heterogeneous soluble TM fragments circulate in the plasma and are found at increased levels in various diseases such as cardiovascular disease and diabetes, and in ischemic and/or inflammatory endothelial injuries. The anticoagulant function of these soluble fragments has not been measured in healthy individuals or in patients. Using an immobilized monoclonal antibody against TM and a microtiter plate format, an assay was designed to capture the soluble TM fragments in plasma and measure their cofactor activity in the thrombin-mediated activation of protein C. In addition, soluble TM antigen levels were measured by enzyme-linked immunosorbent assay. Both assays were used to investigate a group of healthy blood donors. TM fragments released into plasma were shown to retain significant cofactor activity, and reference intervals for healthy men and women were established. Furthermore, a statistically significant correlation was observed between soluble TM antigen levels and soluble TM cofactor activity. This notwithstanding, soluble TM activity only accounted for a minor part of all variation in soluble TM antigen levels (R2 = 22% in men and R2 = 16% in women).
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PMID:Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. 1586 94

Thrombomodulin is a membrane-bound protein that plays an active role in the blood coagulation system by binding thrombin and initiating the protein C anticoagulant pathway. Solulin is a recombinant soluble derivative of human thrombomodulin. It is used for the treatment of thrombotic disorders. To evaluate the production of this pharmaceutical protein in plants, expression vectors were generated using four different N-terminal signal peptides. Immunoblot analysis of transiently transformed tobacco leaves showed that intact Solulin could be detected using three of these signal peptides. Furthermore transgenic tobacco plants and BY2 cells producing Solulin were generated. Immunoblot experiments showed that Solulin accumulated to maximum levels of 115 and 27 microg g(-1) plant material in tobacco plants and BY2 cells, respectively. Activity tests performed on the culture supernatant of transformed BY2 cells showed that the secreted Solulin was functional. In contrast, thrombomodulin activity was not detected in total soluble protein extracts from BY2 cells, probably due to inhibitory effects of substances in the cell extract. N-terminal sequencing was carried out on partially purified Solulin from the BY2 culture supernatant. The sequence was identical to that of Solulin produced in Chinese hamster ovary cells, confirming correct processing of the N-terminal signal peptide. We have demonstrated that plants and plant cell cultures can be used as alternative systems for the production of an active recombinant thrombomodulin derivative.
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PMID:Production of an active recombinant thrombomodulin derivative in transgenic tobacco plants and suspension cells. 1614 33

Factor Va is the critical cofactor for prothrombinase assembly required for timely and efficient prothrombin activation. In the absence of a complete crystal structure for the cofactor, Pellequer et al. [(2000) Thromb. Haemostasis 84, 849-857] proposed an incomplete homology model of factor Va (it lacks 46 amino acids from the carboxyl terminus of the heavy chain), which is a static model in a vacuum. A recently published X-ray structure of activated protein C (APC) inactivated bovine factor Va(i) (without the A2 domain) suggests a completely new arrangement of the C1 and C2 domains as compared with the previously published structure of the recombinant C1 and C2 domains. Our aims were (a) to exchange the C1 and C2 domains of the homology model with the modified bovine C1 and C2 domains using the X-ray structure as a template, (b) to determine by computation the three-dimensional model for the carboxyl-terminal peptide of the factor Va heavy chain (Ser(664)-Arg(709)) and incorporate it into the incomplete model, (c) to obtain a complete model of the cofactor folded in solution that might account for its physiological functions and interactions with other components of prothrombinase, and (d) to use the model in order to understand the mechanism of factor Va inactivation by APC. In the first step a sequence alignment of the human and bovine C1 and C2 domains was performed followed by amino acid changes in the three-dimensional structure where the sequences were not identical. The new model of the C1 and C2 domains was then attached to the homology model. The analysis of the MD simulation data revealed that several domains of the cofactor were significantly displaced during simulation. Using our completed model of human factor Va, we are also demonstrating for the first time that cleavage of membrane-bound normal factor Va as well as membrane-bound factor V(LEIDEN) by APC at Arg(306) is required for the dissociation of the A2 domain from the rest of the molecule. Thus, differences in the inactivation rates of the two cofactor molecules are due to differences in the rate of cleavage at Arg(306). The data demonstrate that our model represents the foundation for the establishment of a complete prothrombinase complex model, which might be successful in describing accurately the ternary protein-protein interaction and thus accounts for experimental observations.
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PMID:Completed three-dimensional model of human coagulation factor va. Molecular dynamics simulations and structural analyses. 1618 76

The acquisition of effector functions by naive CD8 T cells following TCR engagement is thought to occur sequentially with full functionality being gained only after the initiation of division. We show that naive CD8 T cells are capable of immediate effector function following TCR engagement, which stimulates the rapid production of TNF-alpha. Stimulation of splenocytes from naive mice of differing genetic backgrounds with anti-CD3epsilon mAb resulted in significant production of TNF-alpha by naive CD8 T cells within 5 h. Moreover, naive lymphocytic choriomeningitis virus-specific TCR-transgenic CD8 T cells stimulated with either their cognate peptide ligand or virus-infected cells produced TNF-alpha as early as 2 h poststimulation, with production peaking by 4 h. Naive CD8 T cells produced both membrane-bound and soluble TNF-alpha. Interfering with TNF-alpha activity during the initial encounter between naive CD8 T cells and Ag loaded dendritic cells altered the maturation profile of the APC and diminished the overall viability of the APC population. These findings suggest that production of TNF-alpha by naive CD8 T cells immediately after TCR engagement may have an unappreciated impact within the local environment where Ag presentation is occurring and potentially influence the development of immune responses.
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PMID:Rapid production of TNF-alpha following TCR engagement of naive CD8 T cells. 1621 Jun 7

The Ig-like transcript (ILT)3 is crucial to the tolerogenic activity acquired by dendritic cells exposed to allospecific T suppressor (Ts) cells. We have explored the immunomodulatory property of the extracellular region of ILT3 using a cytoplasmic deletion mutant of ILT3 (ILT3delta), expressed as membrane-bound ILT3 on KG1 cells, and a rILT3-Fc fusion protein. We found that both membrane-bound and soluble ILT3 inhibited T cell proliferation in primary and secondary MLC inducing anergy in CD4+ Th cells and suppressing the differentiation of IFN-gamma-producing CD8+ CTL. Furthermore, membrane-bound and soluble ILT3 induced the differentiation of CD8+ FOXP3+ Ts cells in primary 7-day MLC. The suppressive activity of these CD8+ Ts cells is alloantigen specific and mediated by their capacity to induce the up-regulation of ILT3 and down-regulation of costimulatory molecules such as CD86 in APC from the stimulator used for priming, but not on control HLA-mismatched APC. Our finding that ILT3-Fc has potent immunosuppressive activity in vitro and that it acts on T cells only upon activation suggests the possibility that this agent may be of use for specific suppression of the immune response in autoimmunity or transplantation.
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PMID:Recombinant Ig-like transcript 3-Fc modulates T cell responses via induction of Th anergy and differentiation of CD8+ T suppressor cells. 1649 35

Thrombomodulin (TM) is a cell membrane-bound glycoprotein that functions as a thrombin cofactor in the activation of protein C. Its protein structure includes a N-terminal lectin-like domain (D1), 6 epidermal growth factor repeats (D2), a serine-threonine-rich region (D3), a transmembrane domain (D4) and a short cytoplasmic tail (D5). Recent studies have demonstrated the direct effect of TM on cellular proliferation, adhesion and inflammation. In the study, we investigated the role of TM in vascular remodeling and neointima formation in a mouse carotid ligation model. TM expressions on the endothelium, neointima and media were examined in the ligated carotid artery by immunohistochemistry and quantitative real-time reverse transcription PCR. Endothelial TM expression decreased after ligation and appeared later in the media and neointima, which is quite similar to the appearance of TM in the human atherosclerotic process. Recombinant TMD123 was prepared. It was effective for thrombin-dependent protein C activation and the inhibition of leukocyte adhesion to the vessel wall after carotid ligation. Recombinant TMD123 and saline was administered immediately before and after carotid ligation. The TM-treated arteries demonstrated significantly less arterial dilatation (30279 +/- 12605 vs 73789 +/- 15073 microm(2), p < 0.05) in response to less neointima formation (14179 +/- 6538 vs 42227 +/- 8754 microm(2), p < 0.05) at 4 weeks after ligation. Our data indicated that there was a compensatory increase in TM expression in the media and neointima in relation to the reduced endothelial TM after carotid ligation. Early recombinant TM treatment in mice undergoing carotid ligation altered vascular remodeling and decreased the severity of neointima formation.
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PMID:Thrombomodulin plays an important role in arterial remodeling and neointima formation in mouse carotid ligation model. 1654 71

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