High Molecular Weight Kininogen Is Cleaved by FXIa at Three Sites: Arg409-Arg410, Lys502-Thr503 and Lys325-Lys326

Mauron, Thomas; Lämmle, Bernhard; Wuillemin, Walter A.

doi:10.1055/s-0037-1613897

Cited by 17 publications

(19 citation statements)

References 22 publications

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“…The intermediate of the light chain was not visible ( Figure 3B). The incubation of HK with FXIa for more than 1 h resulted in the disappearance of the mature light chain, presumably by further cleavage at Lys 502 -Thr 503 removing both surface binding regions from the light chain as reported earlier (Scott et al, 1985;Mauron et al, 2000). This cleavage step was not observed with PHBSP or PKβ.…”

Section: Cleavage Of Hmw Kininogen In Solutionsupporting

confidence: 71%

“…Treatment of HK with PHBSP for prolonged time partially lead to further cleavage of the light chain in domain D5 H , removing at least the first surface and cell binding region from HKa. Unlike PK and PHBSP, FXIa inactivates the cofactor by removing both surface binding regions from the light chain, hence separating the D5 H from the D6 H domain and thus abolishing the procoagulatory function of HKa (Scott et al, 1985;Mauron et al, 2000). The removal of only the N-terminal part of the surface binding domain D5 H by PHBSP might be involved in the regulation of HK functions at cell surfaces where interactions with peptides up to Lys 480 are required, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…In plasma HK is mostly found in complex with PK or FXI, mediated by domain D6 (Mandle et al, 1976;Thompson et al, 1977). The activated forms of both zymogens, plasma kallikrein (PK) and FXIa, can cleave the pro-cofactor HK to finally release the vasoactive peptide bradykinin (BK), although the cleavage patterns differ (Scott et al, 1985;Mauron et al, 2000). Unlike FXIa, BK release by plasma kallikrein leaves behind activated kininogen (HKa) which has anti-adhesive and antiangiogenic functions (Colman, 2001).…”

Section: Introductionmentioning

confidence: 99%

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The Hyaluronan-Binding Serine Protease from Human Plasma Cleaves HMW and LMW Kininogen and Releases Bradykinin

Etscheid¹,

Beer²,

Fink³

et al. 2002

Biological Chemistry

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Section: Cleavage Of Hmw Kininogen In Solutionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Hyaluronan-Binding Serine Protease from Human Plasma Cleaves HMW and LMW Kininogen and Releases Bradykinin

Etscheid¹,

Beer²,

Fink³

et al. 2002

Biological Chemistry

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“…Alternatively, heparin binding to ATIII may have potentiated its inhibitory effect even in the absence of FXIa binding to heparin. In support of this is a recent abstract describing enhancement of C1-INH inhibition of FXIa by low molecular weight heparins that are of insufficient length to support a template mechanism (44).…”

Section: The Effect Of Alanine or Glutamic Acid Substitutions Betweenmentioning

confidence: 83%

Characterization of a Heparin Binding Site on the Heavy Chain of Factor XI

Zhao

Abdel-Razek

Sun

et al. 1998

Journal of Biological Chemistry

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The glycosaminoglycan heparin enhances several reactions involving coagulation factor XI (FXI) including activation of FXI by factor XIIa, thrombin, and autoactivation; and inactivation of activated FXI (FXIa) by serine protease inhibitors. We examined the effect of heparin on inhibition of FXIa by the inhibitors C1-inhibitor (C1-INH) and antithrombin III (ATIII). Second order rate constants for inhibition in the absence of heparin were 1.57 ؋ 10 3 and 0.91 ؋ 10 3 M ؊1 s ؊1 for C1-INH and ATIII, respectively. Therapeutic heparin concentrations (0.1-1.0 units/ml) enhanced inhibition by ATIII 20 -55-fold compared with 0.1-7.0-fold for C1-INH. For both inhibitors, the effect of heparin over a wide range of concentrations (10 ؊1 to 10 5 units/ml) produced bellshaped curves, demonstrating that inhibition occurs by a template mechanism requiring both inhibitor and protease to bind to heparin. This implies that FXI/XIa contains structural elements that interact with heparin. Coagulation factor XI (FXI) 1 is the zymogen of a plasma serine protease that contributes to normal hemostasis by activating factor IX through limited proteolysis, in a calcium-dependent manner (1-3). The regulation of activated FXI (FXIa) appears to involve several plasma serine protease inhibitors (serpins). Initial work suggested that ␣ 1 -antitrypsin (4 -6) is the predominant plasma inhibitor of FXIa with some contribution from antithrombin III (ATIII) (5, 7, 8). Recent reports using monoclonal antibody-based enzyme-serpin complex capture techniques disagree with the earlier findings, and indicate a predominant role for C1-inhibitor (C1-INH) and a significant contribution from ␣ 2 -anti-plasmin (9). The important anticoagulant drug heparin, a highly sulfated glycosaminoglycan isolated from bovine or porcine lung and gut, enhances the inhibition of FXIa by the inhibitors ATIII (8, 10), protease nexin II (11), and C1-INH (12). Although most studies indicate that saturating concentrations of heparin enhance ATIII-mediated inhibition 20 -40-fold (8, 10, 13), a recent report indicates a considerably smaller effect and proposes that heparin's primary anticoagulant effect on FXIa is through C1-INH (12).There is evidence that FXIa inhibition by ATIII in the presence of heparin proceeds by a template mechanism in which both protease and serpin are approximated by binding to the glycosaminoglycan (13,14). This process is exemplified by heparin-enhanced inhibition of the coagulation protease thrombin by ATIII (14,15). A template mechanism has also been demonstrated for autoactivation of FXI in the presence of polyanions such as heparin and the synthetic polysaccharide dextran sulfate (16,17). The template mechanism implies that FXIa contains structural elements involved in interactions with heparin. Numerous proteins have been described that interact with heparin and other glycosaminoglycans, many of which contain clusters of basic amino acids that form positively charged binding sites for the negatively charged glycosaminoglycan (18). The nature of these...

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“…In addition to kallikrein, HK is also subject to proteolytic hydrolysis by enzymes such as plasmin [50] and neutrophil elastase [51]. A particularly interesting finding is that HK can be cleaved by factor XIa into three peptides, one of the which contains the amino acid sequence between Arg410-Thr503, which is similar to the D5 domain [52]. This result suggests that D5 might circulate in plasma under conditions of increased proteolysis such as cancer.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Angiogenesis by the Kallikrein-Kinin System

Colman¹

2006

CPD

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High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.

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High Molecular Weight Kininogen Is Cleaved by FXIa at Three Sites: Arg409-Arg410, Lys502-Thr503 and Lys325-Lys326

Cited by 17 publications

References 22 publications

The Hyaluronan-Binding Serine Protease from Human Plasma Cleaves HMW and LMW Kininogen and Releases Bradykinin

The Hyaluronan-Binding Serine Protease from Human Plasma Cleaves HMW and LMW Kininogen and Releases Bradykinin

Characterization of a Heparin Binding Site on the Heavy Chain of Factor XI

Regulation of Angiogenesis by the Kallikrein-Kinin System

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