UNIPROT:P02749 - FACTA Search

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Query: UNIPROT:P02749 (beta2-glycoprotein I)
836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The high affinity of human plasma beta2-glycoprotein I (beta(2)GPI), also known as apolipoprotein-H (ApoH), for negatively charged phospholipids determines its implication in a variety of physiological pathways, including blood coagulation and the immune response. beta(2)GPI is considered to be a cofactor for the binding of serum autoantibodies from antiphospholipid syndrome (APS) and correlated with thrombosis, lupus erythematosus and recurrent fetal loss. We solved the beta(2)GPI structure from a crystal form with 84% solvent and present a model containing all 326 amino acid residues and four glycans. The structure reveals four complement control protein modules and a distinctly folding fifth C-terminal domain arranged like beads on a string to form an elongated J-shaped molecule. Domain V folds into a central beta-spiral of four antiparallel beta-sheets with two small helices and an extended C-terminal loop region. It carries a distinct positive charge and the sequence motif CKNKEKKC close to the hydrophobic loop composed of residues LAFW (313-316), resulting in an excellent counterpart for interactions with negatively charged amphiphilic substances. The beta(2)GPI structure reveals potential autoantibody-binding sites and supports mutagenesis studies where Trp316 and CKNKEKKC have been found to be essential for the phospholipid-binding capacity of beta(2)GPI.
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PMID:Crystal structure of human beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome. 1056 35

Prothrombin time (PT) is routinely used to monitor oral anticoagulant treatment in patients with the antiphospholipid antibody syndrome (APS). The fact that PT is a phospholipid (PL)-dependent coagulation test raises the possibility that lupus anticoagulant (LA) might interfere with this test, thus complicating the control of anticoagulant treatment. The effect of 6 affinity-purified preparations of anti- (a)beta2-glycoprotein I (GPI) antibodies with LA activity on the PT was tested. Instead of prolonging PT as expected, the abeta2-GPI antibodies reduced the PT of both normal plasma and anticoagulated plasma by a mean of 2.4 seconds and 5.6 seconds, respectively. This effect was also observed using other 5 commercially available preparations of thromboplastin. The abeta2-GPI-mediated reduction in PT was dose-dependent and was lost upon removal of beta2-GPI. The failure of abeta2-GPI antibodies to express LA activity in PT was found to depend on the fact that calcium ions were added together with PL at the beginning of the assay. In fact, modification of the standard diluted Russell viper venom time (dRVVT) test by adding calcium ions together with PL resulted in a loss of abeta2-GPI anticoagulant activity. The procoagulant effect was not as evident in an assay that used stimulated monocytes as a source of thromboplastin. These results show that abeta2-GPI antibodies exhibit an 'in vitro' procoagulant effect in PT and an anticoagulant effect in dRVVT only when the interaction with their antigen and PL occurs in the absence of calcium ions.
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PMID:Procoagulant effect of anti-beta2-glycoprotein I antibodies with lupus anticoagulant activity. 1057 96

The ability of beta(2)-glycoprotein I (formerly referred to as apolipoprotein H) to act as an autoantigen for antibodies from patients with antiphospholipid syndrome is dependent upon its binding in vivo to anionic phospholipid surfaces or to surfaces in vitro which mimic their surface characteristics. The ability of the autoepitope(s) of beta(2)-glycoprotein I to be exposed by binding a short-chain (6-carbon), anionic phospholipid has not been explored. Here, we describe our studies of the hololipoprotein generated by reacting beta(2)-glycoprotein I with dicaproyl phosphatidylserine. The formation of the complex is accompanied by inhibition of beta(2)-glycoprotein I binding to phospholipid-coated polystyrene surfaces, with 50% reduction in binding occurring at about 10 mM. At concentrations >10 mM, dicaproyl phosphatidylserine also displaces beta(2)-glycoprotein I bound to anionic phospholipid surfaces. Physicochemical studies suggest that at DCPS concentrations >6 mM, the solutions are colloidal and that beta(2)-glycoprotein I forms a supramolecular complex with organized phospholipid structures. Using a standard human autoimmune anti-beta(2)-glycoprotein I plasma, as well as a series of six additional sera from patients with antiphospholipid syndrome, the complex did not generate a detectable epitope. We conclude that lipid binding, per se, is not sufficient for the presentation of the epitope(s) of beta(2)-glycoprotein I or its recognition by autoantibodies from patients with antiphospholipid syndrome.
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PMID:The hololipoprotein complex of beta(2)-glycoprotein I and dicaproyl phosphatidylserine. 1059 9

New evidence indicates that antibodies to beta2-glycoprotein I (anti-beta2GPI) or to human prothrombin (anti-II)(or to both of these) are specific markers of the antiphospholipid syndrome (APS). They have been mainly associated with thrombotic complications in patients with APS. However, some studies have reported that elevated levels of anti-II, but not of anfi-beta2GPI, imply a risk of venous thrombosis (VT) or arterial thrombosis (AT) in subjects with no previous thrombosis and no antiphospholipid antibodies (aPL) by ELISA. The present study Included 180 patients with a history of thrombosis, 83 of them without aPL (group I) and the remaining 97 diagnosed as having APS (group II). Anti-beta2GPI was found in only 1 of the 83 patients from group I but was found in approximately 50% of those from group II (P < .0001). In contrast, positive anti-II was detected with a high prevalence in patients from group I (VT, 22.6%; AT, 26.7%) and in those from group II (VT, 37.5%; AT, 14.6%). No statistical differences were found in the prevalence of anti-II between the two groups of patients. On the other hand, such a difference was significant when compared with results in a normal group (1/67, 1.4%, P < .0001). These data Indicate that anti-II occurs frequently in patients with previous thrombosis either with or without lupus anticoagulant activity. Accordingly, testing of anti-II might be clinically useful in the evaluation for thrombophilla.
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PMID:Occurrence of anti-prothrombin and anti-beta2-glycoprotein I antibodies in patients with history of thrombosis. 1059 89

The mechanism of thrombosis in patients with antiphospholipid syndrome is not clear. To investigate it, we examined the effect of monoclonal anticardiolipin (aCL) antibodies and beta2-glycoprotein I (beta2-GPI), which is required for formation of the aCL epitopes, on activated protein C (APC) and on fibrinolytic activity. First, APC activities were measured in the presence and absence of beta2-GPI or gamma M immunoglobulin (IgM) monoclonal aCLs (EY1C8 and EY2C9), or both, established from peripheral blood lymphocytes obtained from a patient with aCL. beta2-GPI exhibited a procoagulant activity by inhibiting APC activity as well as an anticoagulant activity by inhibiting thrombin generation. Any further inhibition of APC activity was caused by monoclonal aCL, and then only in the presence of beta2-GPI. The remaining tissue plasminogen activator (t-PA) of the sample consisting of beta2-GPI, two-chain recombinant t-PA, and plasminogen activator inhibitor (PAI)-1 was measured by a chromogenic assay using the synthetic substrate S-2251, Glu-plasminogen, and soluble fibrin monomer. beta2-GPI protected t-PA activity from inhibition by PAI-1. However, monoclonal aCLs (EY1C8 and EY2C9) inhibited the effect of beta2-GPI on fibrinolytic activity; that is, monoclonal aCLs inhibited fibrinolytic activity by elevating PAI-1 activity. Thrombosis in patients with aCL can be explained in part by both the inhibition of APC anticoagulant activity and the impairment of fibrinolytic activity by aCL.
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PMID:The putative mechanism of thrombosis in antiphospholipid syndrome: impairment of the protein C and the fibrinolytic systems by monoclonal anticardiolipin antibodies. 1062 10

Using molecular typing, we evaluated the strength of class II HLA associations in 67 Greek patients with antiphospholipid syndrome (APS), 54 of whom had antibodies against beta2-glycoprotein I (beta2GPI), as compared to 246 controls. To further clarify and delineate HLA associations of the beta2GPI response, we combined these data with individual patient data from three other ethnic groups including an additional 74 patients with beta2GPI response and 403 ethnically matched controls of white, African-American, and Mexican-American origin in a formal meta-analysis. The major alleles associated with anti-beta2GPI response are HLA-DQA1*03 (in particular *0301) and the HLA-DRB1*1302-DQB1*0604 haplotype, while protection against developing an anti-beta2GPI response is related primarily to the HLA-DRB1*0101-DQA1*0101 haplotype and the HLA-DRB1*1101 allele. These effects are not significantly heterogeneous across ethnic groups. The previously observed association with HLA-DQB1*0302 may simply reflect linkage disequilibrium with HLA-DQA1*0301 and the previously reported HLA-DQB1*06 effect is limited to HLA-DQB1*0604/0605, while HLA-DQB1*0602 is unlikely to be important. The meta-analysis clearly documents that the anti-beta2GPI response is determined by a few specific class II alleles and haplotypes.
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PMID:HLA associations of anti-beta2 glycoprotein I response in a Greek cohort with antiphospholipid syndrome and meta-analysis of four ethnic groups. 1062 42

Apoptosis (programmed cell death) is accompanied by loss of phospholipid asymmetry, i.e., translocation of aminophospholipids such as phosphatidylserine to the outer leaflet of the plasma membranes, which results in recognition of these cells by macrophages. In the present study, I studied on the involvement of beta 2-glycoprotein I (beta 2-GPI) and anti-beta 2-GPI antibodies in apoptotic lymphocytes. By flowcytometric analysis, I demonstrated that beta 2-GPI could bind to a human T cell line, Jurkat cells, treated with an anti-Fas antibody, CH11. beta 2-GPI-bound cells were detected 2 hr later after anti-Fas treatment and the most cells were bound to beta 2-GPI by 6 hr later. The accumulation of beta 2-GPI-bound cells paralleled with morphological changes and DNA fragmentation of the cells. I also demonstrated that anti-beta 2-GPI antibodies and a beta 2-GPI-dependent anti-cardiolipin antibody, established from a patient with antiphospholipid syndrome, could recognize beta 2-GPI-bound Jurkat cells treated with anti-Fas-antibody. These results imply that beta 2-GPI and anticardiolipin antibody may have a role in the clearance of apoptotic cells from the blood stream.
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PMID:[Investigation of binding capacity of beta 2-glycoprotein I with anti-beta 2-glycoprotein I antibodies in lymphocytes undergoing apoptosis]. 1073 59

Beta-2-glycoprotein I (beta2GP1) has been implicated as the primary antigenic target in antiphospholipid syndrome. To study the role beta2GP1 antibodies play in thrombosis associated with this syndrome, the clearance and binding of phosphatidylserine (PS)-containing target membranes were monitored in beta2GP1-immune mice. Clearance in immune mice (T(1/2)4.8 min) was faster than in normal mice (T(1/2)11.0 min). Analysis of PS vesicles recovered from immune mice by sequencing and Western blotting showed the presence of bound beta2GP1 and autologous antibody, respectively. Bleeding times in immune mice were approximately 30% shorter than in control mice. In vitro clotting times, however, were the same in both populations. To determine if the in vivo results could be attributed to the interaction of autoantibodies with the vascular endothelium, the binding of PS-containing target membranes to normal and apoptotic endothelial cells was studied. While endothelial cells bound PS vesicles, beta2GP1 reduced uptake by approximately 50% in both normal and apoptotic endothelium. In the presence of beta2GP1 antibodies, however, uptake in apoptotic cells, but not normal cells, increased by more than two-fold. These results suggest that thrombosis in antiphospholipid syndrome could, in part, be due to antibody-dependent cross-linking of beta2GP1 bound to PS-expressing cells and the vascular endothelium.
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PMID:Phosphatidylserine expression on cell surfaces promotes antibody-dependent aggregation and thrombosis in beta2-glycoprotein I-immune mice. 1075 84

Antiphospholipid antibodies (aPLs) are associated with an increased incidence of thrombosis, but the mechanisms responsible for thrombosis are unclear. The present study investigated the effect of both beta2-glycoprotein I (beta2-GPI) and aPLs on the activity of extrinsic fibrinolysis. The remaining tissue-plasminogen activator (t-PA) of the sample consisting of beta2-GPI, two-chain recombinant t-PA, plasminogen activator inhibitor (PAI) -1 was measured by a chromogenic assay using synthetic substrate S-2251, Glu-plasminogen, and soluble fibrin monomer. Without PAI-1, beta2-GPI did not affect t-PA activity. When 14.3 ng/ml PAI-1 was added to 3.6 U/ml t-PA, the remaining t-PA activity was increased from 48.9% to 60.4% by the addition of beta2-GPI (190 microg/ml). The effect of beta2-GPI did not require phospholipids. The beta2-GPI seems to protect t-PA activity from the inhibition by PAI-1. When monoclonal anticardiolipin antibodies (aCLs), EY1C8, and EY2C9, which were established from a patient with antiphospholipid syndrome, were further added to the mixture with a diluted phospholipid (Platelin) to investigate the influence of aPL, the remaining t-PA activity decreased to 50.1 and 80.7%. Monoclonal aCLs appeared to inhibit the effect of beta2-GPI, that is, these monoclonals inhibited the fibrinolytic activity by an elevation in PAI-1 activity. These results suggest the possibility that the impairment of fibrinolytic activity by aCLs is one of reasons for the increased incidence in thrombosis in patients with aCLs.
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PMID:Effects of beta2-glycoprotein I and monoclonal anticardiolipin antibodies on extrinsic fibrinolysis. 1080 87

Antiphospholipid antibodies are well recognized as associated with serious clinical complications such as arterial and venous thrombosis and recurrent spontaneous abortion. These complications are collectively called antiphospholipid syndrome(APS). The mechanisms responsible for the thrombosis are unclear. We reported three mechanisms. beta 2-glycoprotein I(beta 2GPI) inhibited activated protein C(APC) activity and, furthermore, APC activity decreased by the addition of monoclonal aCL and beta 2GPI. Monoclonal anticardiolipin antibodies(aCL) seemed to enhance the inhibition of APC procoagulant activity caused by beta 2GPI. Monoclonal aCL in the presence of beta 2GPI also increased the activity of plasminogen activator inhibitor(PAI)-1 in the mixture of tissue-plasminogen activator(t-PA) and PAI-1 by inhibiting the function of beta 2GPI, which increased the remaining t-PA activity in the mixture. The formation of thrombin-antithrombin complexes(TAT) in APS was impaired. The level of TAT in APS did not increase, however the level of prothrombin fragment 1 + 2 (F1 + 2) increased. Therefore, free thrombin present in patients' blood may contribute to thrombosis in APS. These reports indicate that thrombosis in APS may be caused by several thrombogenic factors that stimulate aCL.
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PMID:[Antiphospholipid antibodies and thrombosis: the putative mechanisms of hypercoagulable state in patients with anticardiolipin antibody]. 1081 Aug 73

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