A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase.

Agostini, Ariane de; Patston, Philip A.; Marottoli, V; Carrel, Stefan; Harpel, Peter C.; Schapira, Marc

doi:10.1172/jci113650

Cited by 37 publications

(23 citation statements)

References 34 publications

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“…Experimental details and the derived kinetic constants are given in Table 1. corroborated by reports on monoclonal antibodies recognizing neoantigenic epitopes on C1 inhibitor and PAI-1 generated both by cleavage of the reactive center loop and by complex formation [22,23]. Mammalian and Fusarium trypsins are very similar in their secondary structural elements and overall conformation but significant differences are observed in the active site region [24].…”

Section: Discussionsupporting

confidence: 60%

Inhibition of coagulation factors by recombinant barley serpin BSZx

et al. 1996

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Barley serpin BSZx is a potent inhibitor of trypsin and chymotrypsin at overlapping reactive sites (Dahl, S.W., Rasmussen, S.K. and Hejgaard, J. (1996) J. Biol. Chem., in press). We have now investigated the interactions of BSZx with a range of serine proteinases from human plasma, pancreas and leukocytes, a fungal trypsin and three subtilisins. Thrombin, plasma kallikrein, factor Vllaltissue factor and factor Xa were inhibited by BSZx at heparin independent association rates (kass) of 4.5 x 103-1.3 x 105 M -l s i at 22°C. Only factor Xa turned a significant fraction of BSZx over as substrate. Complexes of these proteinase with BSZx resisted boiling in SDS, and amino acid sequencing showed that cleavage in the reactive center loop only occurred after PI Arg. Activated protein C and leukocyte clastase were slowly inhibited by BSZx (kass = I-2X 102 M -l s -t) whereas factor Xlla, urokinase and tissue type plasminogen activator, plasmin and pancreas kallikrein and elastase were not or only weakly affected. The inhibition pattern with mammalian proteinases reveal a specificity of BSZx similar to that of antithrombin III. Trypsin from Fusarium was not inhibited while interaction with subtilisin Carlsberg and Novo was rapid but most BSZx was cleaved as a substrate. Identification of a monoclonal antibody specific for native BSZx indicate that complex formation and loop cleavage result in similar conformational changes.

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Section: Discussionsupporting

confidence: 60%

Inhibition of coagulation factors by recombinant barley serpin BSZx

et al. 1996

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“…Serpins undergo major conformational changes upon interaction with a proteinase (38,47). These structural alterations coincide with the exposure of neo-epitopes (32,48,49). We have produced MAb that specifically react with neo-epitopes present on both complexed and cleaved a,AT and a,ACT, in order to study the inactivation of these serpins in human diseases (23.24).…”

Section: Discussionmentioning

confidence: 87%

Proteolytic inactivation of α₁‐antitrypsin and α₁‐antichymotrypsin by neutrophils in arthritic joints

Abbink

Kamp

Nuijens

et al. 1993

Arthritis & Rheumatism

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Objective. In vitro, activated neutrophils create a microenvironment in which proteinase inhibitors are inactivated through the coordinate action of reactive oxygen species and released elastase. We investigated whether such a mechanism may contribute to the destruction of the joint tissues in arthritis.Methods. We analyzed the state of a,-antitrypsin (a,AT) and a,-antichymotrypsin (a,ACT), the two major inhibitors of the neutrophilic serine proteinases, in synovial fluid (SF) from patients with inflammatory arthropathies (n = 71) and osteoarthritis (OA) (n = ll), and related the results to neutrophil activation in SF.Results. The ratio of functional to antigenic levels of q A T in SF of patients with inflammatory joint diseases was similar to that of alAT in normal plasma, whereas that of a,ACT was significantly decreased. Patients with inflammatory arthropathies had significantly higher levels of inactivated a,AT (ialAT) and inactivated a,ACT (ia,ACT) in SF (as determined with monoclonal antibodies specific for the inactivated [i.e., proteolytically inactivated and/or complexed] forms of these inhibitors) than patients with OA (P < 0.005).Inactivated a,AT and ia,ACT levels corresponded to 0.341% and 3-99%, respectively, of the total amount of these inhibitors in SF. Most

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“…This indicates that the epitopes recognized by the antibodies are not located in the near vicinity of the active site residues Arg346-Met347 of PAI-I. de Agostini et al [28,29] nor Nuijens et al [30] provided information on the functional effects of their monoclonal antibodies.…”

Section: Detection O]common Neoantigenic Epitopes In Various Pal1mentioning

confidence: 99%

Characterization of common neoantigenic epitopes generated in plasminogen activator inhibitor‐1 after cleavage of the reactive center loop or after complex formation with various serine proteinases

Debrock

Declerck

1995

FEBS Letters

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Plasminogen activator inhibitor-I (PAl-l), an important risk factor for thrombotic diseases, is a member of the superfamily of serine proteinase inhibitors. To define structural rearrangements occurring during interaction between PAI-I and its target proteinases we have raised monoclonal antibodies against the PAI-IIt-PA complex. Thirteen out of 401 monoclonal antibodies reacted preferentially with the PAI-IIt-PA complex as compared to free PAI-I or free t-PA. Detailed characterization revealed the presence of two non-overlapping neoantigenic epitopes in the PAI-IIt-PA complex. Both neoantigenic epitopes were also exposed after complex formation between PAI-I and either urokinase-type plasminogen activator, plasmin or thrombin as well as after cleavage of the reactive site loop of non-inhibitory substrate type PAI-I variants. Thus, we have identified two neoantigenic epitopes, localized entirely in PAl-l, and commonly exposed after complex formation of active PAI-I with various proteinases or after cleavage of substrate PAI-I. These monoclonal antibodies should facilitate further studies on the mechanism of interaction between various PAI-I forms and its target proteinases.

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A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase.

Cited by 37 publications

References 34 publications

Inhibition of coagulation factors by recombinant barley serpin BSZx

Inhibition of coagulation factors by recombinant barley serpin BSZx

Proteolytic inactivation of α₁‐antitrypsin and α₁‐antichymotrypsin by neutrophils in arthritic joints

Characterization of common neoantigenic epitopes generated in plasminogen activator inhibitor‐1 after cleavage of the reactive center loop or after complex formation with various serine proteinases

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A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase.

Cited by 37 publications

References 34 publications

Inhibition of coagulation factors by recombinant barley serpin BSZx

Inhibition of coagulation factors by recombinant barley serpin BSZx

Proteolytic inactivation of α1‐antitrypsin and α1‐antichymotrypsin by neutrophils in arthritic joints

Characterization of common neoantigenic epitopes generated in plasminogen activator inhibitor‐1 after cleavage of the reactive center loop or after complex formation with various serine proteinases

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Proteolytic inactivation of α₁‐antitrypsin and α₁‐antichymotrypsin by neutrophils in arthritic joints