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Allen P. Kaplan - One of the best experts on this subject based on the ideXlab platform.
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cytokine and estrogen stimulation of endothelial cells augments activation of the surface bound Prekallikrein high molecular weight kininogen complex implications for hereditary angioedema hae
The Journal of Allergy and Clinical Immunology, 2016Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Allen P. KaplanAbstract:Background When the Prekallikrein-high molecular weight kininogen complex is bound to endothelial cells, Prekallikrein is stoichiometrically converted to kallikrein because of release of heat shock protein-90 (Hsp90). Although bradykinin formation is typically initiated by factor XII autoactivation, it is also possible to activate factor XII either by kallikrein, thus formed, or by plasmin. Objective Because attacks of hereditary angioedema can be related to infection and/or exposure to estrogen, we questioned whether estrogen or cytokine stimulation of endothelial cells could augment release of Hsp90 and Prekallikrein activation. We also tested release of profibrinolytic enzymes, urokinase, and tissue plasminogen activator (TPA) as a source for plasmin formation. Methods Cells were stimulated with agonists, and secretion of Hsp90, urokinase, and TPA was measured in the culture supernatants by ELISA. Activation of the Prekallikrein-HK complex was measured by using pro-phe-arg-p-nitroanilide reflecting kallikrein formation. Results Hsp90 release was stimulated with optimal doses of estradiol, IL-1, and TNF-α (10 ng/mL) from 15 minutes to 120 minutes. TPA release was not augmented by any of the agonists tested but urokinase was released by IL-1, TNF-α, and thrombin (positive control), but not estrogen. Augmented activation of the Prekallikrein-HK complex to generate kallikrein was seen with each agonist that releases Hsp90. Addition of 0.1% factor XII relative to Prekallikrein-HK leads to rapid formation of kallikrein; factor XII alone does not autoactivate. Conclusions IL-1, TNF-α, and estrogen stimulate release of Hsp90 and augment activation of the Prekallikrein-HK complex to generate kallikrein and bradykinin. IL-1 and TNF-α stimulate release of urokinase, which can convert plasminogen to plasmin and represents a possible source for plasmin generation in all types of hereditary angioedema, but particularly hereditary angioedema with normal C1 inhibitor with a factor XII mutation. Both kallikrein and plasmin activate factor XII; kallikrein is 20 times more potent on a molar basis.
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factor xii independent activation of the bradykinin forming cascade implications for the pathogenesis of hereditary angioedema types i and ii
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Anette Bygum, Berhane Ghebrehiwet, Allen P. KaplanAbstract:Background We have previously reported that Prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of Prekallikrein to kallikrein in a zinc-dependent reaction. Objective Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through factor XII. Methods Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from factor XII–deficient plasma by means of immunoadsorption. Results We demonstrate that Prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both factor XII and C1-INH led to conversion of Prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects. Conclusions These results indicate that C1-INH stabilizes the Prekallikrein-HK complex to prevent HK cleavage either by Prekallikrein or by Prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking factor XII activation, although the kallikrein formed can rapidly activate factor XII if it is surface bound.
Werner Mulleresterl - One of the best experts on this subject based on the ideXlab platform.
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characterization of the h kininogen binding site on factor xi a comparison of factor xi and plasma Prekallikrein
Journal of Biological Chemistry, 2002Co-Authors: Thomas Renne, Joost C M Meijers, David Gailani, Werner MulleresterlAbstract:Abstract Factor XI (FXI), the zymogen of the blood coagulation protease FXIa, and the structurally homologous protein plasma Prekallikrein circulate in plasma in noncovalent complexes with H-kininogen (HK). HK binds to the heavy chains of FXI and of Prekallikrein. Each chain contains four apple domains (F1–F4 for FXI and P1–P4 for Prekallikrein). Previous studies indicated that the HK-binding site on FXI is located in F1, whereas the major HK-binding site on Prekallikrein is in P2. To determine the contribution of each FXI apple domain to HK-FXI complex formation, we examined binding of recombinant single apple domain-tissue plasminogen activator fusion proteins to HK. The order of affinity from highest to lowest is F2 ≫ F4 > F1 ≫ F3. Monoclonal antibodies against F2 are superior to F4 or F1 antibodies as inhibitors of HK binding to FXI. Antibody αP2, raised against Prekallikrein, cross-reacts with FXI F2 and inhibits FXI-HK binding with an IC50 of 8 nm. HK binding to a platelet-specific FXI variant lacking the N-terminal half of F2 is reduced > 5-fold compared with full-length FXI. A chimeric FXI molecule in which F2 is replaced by P2 is cleaved within P2 during activation by factor XIIa, resulting in greatly reduced HK binding capacity. In contrast, wild-type FXI is not cleaved within F2, and its binding capacity for HK is unaffected by factor XIIa. Our data show that HK binding to FXI involves multiple apple domains, with F2 being most important. The findings demonstrate a similarity in mechanism for FXI and Prekallikrein binding to HK.
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mapping of the discontinuous h kininogen binding site of plasma Prekallikrein evidence for a critical role of apple domain 2
Journal of Biological Chemistry, 1999Co-Authors: Thomas Renne, Jürgen Dedio, Joost C M Meijers, Dominic Chung, Werner MulleresterlAbstract:Plasma Prekallikrein, a zymogen of the contact phase system, circulates in plasma as heterodimeric complex with H-kininogen. The binding is mediated by the Prekallikrein heavy chain consisting of four apple domains, A1 to A4, to which H-kininogen binds with high specificity and affinity (K(D) = 1.2 x 10(-8) M). Previous work had demonstrated that a discontinuous kininogen-binding site is formed by a proximal part located in A1, a distal part exposed by A4, and other yet unidentified portion(s) of the kallikrein heavy chain. To detect relevant binding segment(s) we recombinantly expressed single apple domains and found a rank order of binding affinity for kininogen of A2 > A4 approximately A1 > A3. Removal of single apple domains in Prekallikrein deletion mutants reduced kininogen binding by 21 (A1), 64 (A2), and 24% (A4), respectively, whereas deletion of A3 was without effect. Transposition of homologous A2 domain from Prekallikrein to factor XI conferred high-affinity kininogen binding from the former to the latter. The principal role of A2 for H-kininogen docking to the Prekallikrein heavy chain was further substantiated by the finding that cleavage of a single peptide bond in A2 drastically diminished the H-kininogen binding affinity. Furthermore, the epitope of monoclonal antibody PKH6 which blocks kallikrein-kininogen complex formation with an IC(50) of 8 nM mapped to the center portion of domain A2. Our data indicate that domain A2 and two flanking sequence segments of A1 and A4 form a discontinuous binding platform for H-kininogen on the Prekallikrein heavy chain. Domain-specific antibodies directed to these critical sites efficiently interfered with contact phase-induced bradykinin release from H-kininogen.
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mapping of the discontinuous kininogen binding site of Prekallikrein a distal binding segment is located in the heavy chain domain a4
Journal of Biological Chemistry, 1996Co-Authors: Heiko Herwald, Robert W. Colman, Thomas Renne, Werner Mulleresterl, Joost C M Meijers, J D Page, Dominic W ChungAbstract:Abstract Prekallikrein, the precursor to the serine proteinase kallikrein, circulates in plasma in an equimolar complex with H-kininogen. The binding to H-kininogen is mediated by the kallikrein heavy chain consisting of four “apple” domains, A1-A4, which attaches to H-kininogen with high specificity and affinity (KD = 83 nM). At least two distinct portions of the kallikrein heavy chain form this H-kininogen binding site: a proximal segment located in the NH2-terminal fragment of the heavy chain encompassing A1, and distal segment(s) located in COOH-terminal fragment spanning domains A2-A4. The proximal binding segment has been located to amino acid positions 56-86 of A1. To precisely map the distal binding segment, we have identified monoclonal antibodies directed to the COOH-terminal fragment which interfere with the H-kininogen-Prekallikrein complex formation. Monoclonal antibody 13G11 binds to recombinant apple domain A4 but not to domain A3 of the Prekallikrein heavy chain. Deletion mutagenesis of domain A4 narrowed down the target epitope of 13G11 to the center portion of domain A4, positions 284-331. Direct binding studies of H-kininogen to various domain A4 constructs revealed that the distal H-kininogen binding portion is located on a segment of 48 residues, which overlaps the 13G11 epitope. Hence the tight interaction of H-kininogen and Prekallikrein is mediated by at least two separate sequence segments located in domains A1 and A4, respectively, of the Prekallikrein heavy chain. The isolated distal binding segment significantly prolongs the partial thromboplastin time of reconstituted Williams plasma thus stressing the critical role of the Prekallikrein-H-kininogen complex formation in the initiation of the endogenous blood coagulation cascade.
Robert W. Colman - One of the best experts on this subject based on the ideXlab platform.
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mapping of the discontinuous kininogen binding site of Prekallikrein a distal binding segment is located in the heavy chain domain a4
Journal of Biological Chemistry, 1996Co-Authors: Heiko Herwald, Robert W. Colman, Thomas Renne, Werner Mulleresterl, Joost C M Meijers, J D Page, Dominic W ChungAbstract:Abstract Prekallikrein, the precursor to the serine proteinase kallikrein, circulates in plasma in an equimolar complex with H-kininogen. The binding to H-kininogen is mediated by the kallikrein heavy chain consisting of four “apple” domains, A1-A4, which attaches to H-kininogen with high specificity and affinity (KD = 83 nM). At least two distinct portions of the kallikrein heavy chain form this H-kininogen binding site: a proximal segment located in the NH2-terminal fragment of the heavy chain encompassing A1, and distal segment(s) located in COOH-terminal fragment spanning domains A2-A4. The proximal binding segment has been located to amino acid positions 56-86 of A1. To precisely map the distal binding segment, we have identified monoclonal antibodies directed to the COOH-terminal fragment which interfere with the H-kininogen-Prekallikrein complex formation. Monoclonal antibody 13G11 binds to recombinant apple domain A4 but not to domain A3 of the Prekallikrein heavy chain. Deletion mutagenesis of domain A4 narrowed down the target epitope of 13G11 to the center portion of domain A4, positions 284-331. Direct binding studies of H-kininogen to various domain A4 constructs revealed that the distal H-kininogen binding portion is located on a segment of 48 residues, which overlaps the 13G11 epitope. Hence the tight interaction of H-kininogen and Prekallikrein is mediated by at least two separate sequence segments located in domains A1 and A4, respectively, of the Prekallikrein heavy chain. The isolated distal binding segment significantly prolongs the partial thromboplastin time of reconstituted Williams plasma thus stressing the critical role of the Prekallikrein-H-kininogen complex formation in the initiation of the endogenous blood coagulation cascade.
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the shape of high molecular weight kininogen organization into structural domains changes with activation and interactions with Prekallikrein as determined by electron microscopy
Journal of Biological Chemistry, 1994Co-Authors: John W Weisel, Chandrasekaran Nagaswami, John L Woodhead, R Dela A Cadena, J D Page, Robert W. ColmanAbstract:Abstract Knowledge of the organization of the kininogen gene and protein structure and function correlations has allowed the development of a model of high molecular weight kininogen. Domains 1-3 on the heavy chain are evolutionarily related to cystatin and the latter two are inhibitors of cysteine proteases. Proteolytic cleavage in domain 4 to release bradykinin causes a conformational change, exposing a surface-binding region (domain 5) on the disulfide-linked light chain. The carboxyl-terminal domain 6 contains a zymogen binding sequence for factor XI and Prekallikrein which, with domain 5, accounts for its cofactor activity. To explore further the domain structure, we have determined the shapes of high molecular weight kininogen and Prekallikrein by electron microscopy of rotary shadowed preparations and computer image processing. High molecular weight kininogen appears to be a linear array of three linked globular regions about 16 nm long, with the two ends also connected by another thin strand. Both Prekallikrein and kallikrein have a compact globular shape, with a subdivision that is sometimes visible. Different functional domains of high molecular weight kininogen were identified by monoclonal antibodies against these regions, as well as ligand binding of Prekallikrein. These studies indicate that one end globular region is the Prekallikrein-binding domain, the other comprises the cysteine protease inhibitor domains and the smaller central nodule is the surface-binding domain. Cleavage of high molecular weight kininogen with plasma kallikrein to yield two-chain high molecular weight kininogen results in a striking change in conformation: the central surface-binding domain swings out so that it is still adjacent to the Prekallikrein-binding domain but no longer in the middle. These structural studies provide insight into the interactions of these proteins and aspects of the mechanisms of their actions.
Takeshi Kambara - One of the best experts on this subject based on the ideXlab platform.
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Activation of human plasma Prekallikrein by Pseudomonas aeruginosa elastase. II. Kinetic analysis and identification of scissile bondof Prekallikrein in the activation
Biochimica et biophysica acta, 1992Co-Authors: Hideaki Tanaka, Yoko Shibuya, Tetsuro Yamamoto, Norikazu Nishino, Sumio Tanase, Yoshimasa Miyauchi, Takeshi KambaraAbstract:Activation of human plasma Prekallikrein by a bacterial metalloendopeptidase, Pseudomonas aeruginosa elastase, was reported (Shibuya et al. (1991) Biochim. Biophys. Acta 1097, 23-27). Details of the activation process were presently studied. The activation accompanied limited proteolysis of a peptide bond inside of a disulfide bridge of Prekallikrein molecule. Amino acid sequencing analysis of the newly generated amino-terminal revealed that the cleavage site was Arg371-Ile372 bond which is the scissile bond in the activation of Prekallikrein with trypsin-type proteinases. A pentapeptide substrate, 2-aminobenzoyl-Ser-Thr-Arg-Ile-Val-4- nitrobenzylamide, which contained the amino acid sequence identical to that around the scissile bond of Prekallikrein was synthesized. Pseudomonal elastase, indeed, hydrolyzed the substrate at Arg-Ile bond with the kinetic parameters of Km = 118 microM, kcat = 1.56/s and kcat/Km = 1.33.10(4)/s M. These results indicated that the Arg371-Ile372 bond was sensitive not only to trypsin-type serine proteinases, but also a bacterial metalloproteinase. Kinetic analysis of the Prekallikrein activation by pseudomonal elastase, however, revealed that the activation rate was slow, though the Km values was good enough to expect an occurrence of this activation in vivo (Km = 248 nM, kcat = 6.8.10(-4)/s, and kcat/Km = 2.7.10(3)/s M). The activation rate of Prekallikrein by pseudomonal elastase in Hageman factor deficient plasma was remarkably improved when the plasma was reconstituted with purified Hageman factor molecule. From the results, a biological significance of the proteinase cascade in the plasma kinin generation was also indicated. The present in vitro study might support the hypothesis that the Hageman factor/kallikrein-kinin system plays an important role in bacterial infection including the pseudomonal one.
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Mechanized assay of plasma Prekallikrein by activation with Pseudomonas aeruginosa elastase and amidolysis of chromogenic substrate.
Clinica chimica acta; international journal of clinical chemistry, 1991Co-Authors: Yoko Shibuya, Tetsuro Yamamoto, Hideaki Tanaka, Umeko Semba, Takeshi Kambara, Hiroaki OkabeAbstract:An automated assay of plasma Prekallikrein is described. Prekallikrein was converted to kallikrein with Pseudomonas aeruginosa elastase, and the hydrolytic activity of kallikrein to H-D-Pro-Phe-Arg-paranitroanilide subsequently measured. The conversion was complete within 8 minutes and the amidolytic activity remained stable at least another 10 min at 37 ° C. This method worked in plasma deficient in Hageman factor (blood coagulation factor XII). Using anti-Prekallikrein antibody and plasma deficient in Prekallikrein, the amidolytic activity generated in normal plasma was identified as due to kallikrein. With plasma samples, the coefficients of variation (CV) for multiple measurements within run (n = 10) and between run (n = 10) were as low as 5.0% and 6.6%, respectively, and the minimum measurable concentration of Prekallikrein in plasma was 10% of the normal level.
Kusumam Joseph - One of the best experts on this subject based on the ideXlab platform.
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cytokine and estrogen stimulation of endothelial cells augments activation of the surface bound Prekallikrein high molecular weight kininogen complex implications for hereditary angioedema hae
The Journal of Allergy and Clinical Immunology, 2016Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Allen P. KaplanAbstract:Background When the Prekallikrein-high molecular weight kininogen complex is bound to endothelial cells, Prekallikrein is stoichiometrically converted to kallikrein because of release of heat shock protein-90 (Hsp90). Although bradykinin formation is typically initiated by factor XII autoactivation, it is also possible to activate factor XII either by kallikrein, thus formed, or by plasmin. Objective Because attacks of hereditary angioedema can be related to infection and/or exposure to estrogen, we questioned whether estrogen or cytokine stimulation of endothelial cells could augment release of Hsp90 and Prekallikrein activation. We also tested release of profibrinolytic enzymes, urokinase, and tissue plasminogen activator (TPA) as a source for plasmin formation. Methods Cells were stimulated with agonists, and secretion of Hsp90, urokinase, and TPA was measured in the culture supernatants by ELISA. Activation of the Prekallikrein-HK complex was measured by using pro-phe-arg-p-nitroanilide reflecting kallikrein formation. Results Hsp90 release was stimulated with optimal doses of estradiol, IL-1, and TNF-α (10 ng/mL) from 15 minutes to 120 minutes. TPA release was not augmented by any of the agonists tested but urokinase was released by IL-1, TNF-α, and thrombin (positive control), but not estrogen. Augmented activation of the Prekallikrein-HK complex to generate kallikrein was seen with each agonist that releases Hsp90. Addition of 0.1% factor XII relative to Prekallikrein-HK leads to rapid formation of kallikrein; factor XII alone does not autoactivate. Conclusions IL-1, TNF-α, and estrogen stimulate release of Hsp90 and augment activation of the Prekallikrein-HK complex to generate kallikrein and bradykinin. IL-1 and TNF-α stimulate release of urokinase, which can convert plasminogen to plasmin and represents a possible source for plasmin generation in all types of hereditary angioedema, but particularly hereditary angioedema with normal C1 inhibitor with a factor XII mutation. Both kallikrein and plasmin activate factor XII; kallikrein is 20 times more potent on a molar basis.
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factor xii independent activation of the bradykinin forming cascade implications for the pathogenesis of hereditary angioedema types i and ii
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Kusumam Joseph, Baby G Tholanikunnel, Anette Bygum, Berhane Ghebrehiwet, Allen P. KaplanAbstract:Background We have previously reported that Prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of Prekallikrein to kallikrein in a zinc-dependent reaction. Objective Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through factor XII. Methods Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from factor XII–deficient plasma by means of immunoadsorption. Results We demonstrate that Prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both factor XII and C1-INH led to conversion of Prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects. Conclusions These results indicate that C1-INH stabilizes the Prekallikrein-HK complex to prevent HK cleavage either by Prekallikrein or by Prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking factor XII activation, although the kallikrein formed can rapidly activate factor XII if it is surface bound.