Identification of residues in the Gla-domain of human factor IX involved in the binding to conformation specific antibodies

Wojcik, E. G. C.; Cheung, Wing Fai; Berg, Marieke Van Den; Linden, I K van der; Stafford, Darrel W.; Bertina, Rogier M.

doi:10.1016/s0167-4838(97)00149-0

Cited by 7 publications

(3 citation statements)

References 58 publications

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“…They have identified regions that undergo ligand-induced conformational transitions (35)(36)(37), served as solid phase immunoaffinity reagents that offer facile release of the antibody-protein complex by the addition of EDTA (14,38), and provided novel inhibitors of protein-membrane interaction (15,16). As an approach to developing an antibody-based therapeutic anti-thrombotic agent, the calcium-specific anti-Factor IX antibody, 10C12, was one of a panel of antibodies identified from a human single-chain variable domain antibody (scFv) library screened for binding to human Factor IX in the presence of calcium ions (13).…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of the Calcium-stabilized Human Factor IX Gla Domain Bound to a Conformation-specific Anti-factor IX Antibody

Huang

Furie

2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Crystal Structure of the Calcium-stabilized Human Factor IX Gla Domain Bound to a Conformation-specific Anti-factor IX Antibody

Huang

Furie

2004

Journal of Biological Chemistry

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“…This approach is supported by several studies employing FIX chimeras with substitutions derived from FVII for epitope mapping of monoclonal and oligoclonal antibodies. 39,40 The strategy using FX/FIX chimeras revealed the presence of patients' IgGs with a significantly lower recognition of the protease domain in the presence of EDTA than in the presence of Ca ϩϩ (Figure 2). Interestingly, one structural feature of the FIX protease domain is the presence of a high-affinity Ca ϩϩ -binding site.…”

Section: Discussionmentioning

confidence: 99%

Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B

Olivier

Lenting²,

Cherel³

et al. 2001

Blood

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Development of inhibitory antibodies is a serious complication of treatment with repeated factor IX infusions in a minority of patients with hemophilia B. Such antibodies detected in 8 patients have been characterized. Typing studies revealed that patients' immune response toward factor IX is highly heterogeneous and involves immunoglobulin G (IgG) antibodies, preferentially IgG1 and IgG4. The preservation of the sequence and the 3-dimensional orientation of the amino acids constituting one epitope are highly important for the assembly of an antibodyantigen complex. To localize the epitopes on the factor IX molecule, an original approach was designed using a set of factor X chimeras carrying regions of factor IX. Results showed that some patients' antibodies were directed against both the domain containing the ␥-carboxy glutamic acid residues (Gla domain) and the protease domain of factor IX. In contrast, no binding was observed to the epidermal growth factor-like domains or to the activation peptide. Functional characterization showed that the purified IgG from patients' serum inhibited the factor VIIIa-dependent activation of factor X. Moreover, patients' IgG directed against the Gla domain inhibited the binding of factor IX to phospholipids as well as the binding of factor VIII light chain to factor IXa. These data demonstrate that inhibitors appearing in patients with severe hemophilia B display specificity against restricted functional domains of factor IX. (Blood. 2001;98:1416-1423)

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“…provided strong evidence that Gla residues can constitute part of an epitope (41)(42)(43)(44). Nevertheless, the defined specificity of the antibodies reported here is more akin to those recognizing the O-phosphorylated forms of tyrosine, serine, threonine, and histidine (39,45).…”

Section: Discussionmentioning

confidence: 70%

Identification and Purification of Vitamin K-dependent Proteins and Peptides with Monoclonal Antibodies Specific for γ-Carboxyglutamyl (Gla) Residues

Brown

Stenberg

Persson

et al. 2000

Journal of Biological Chemistry

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Novel monoclonal antibodies that specifically recognize ␥-carboxyglutamyl (Gla) residues in proteins and peptides have been produced. As demonstrated by Western blot and time-resolved immunofluorescence assays the antibodies are pan-specific for most or all of the Gla-containing proteins tested (factors VII, IX, and X, prothrombin, protein C, protein S, growth arrest-specific protein 6, bone Gla protein, conantokin G from a cone snail, and factor Xa-like proteins from snake venom). Only the Gla-containing light chain of the twochain proteins was bound. Decarboxylation destroyed the epitope(s) on prothrombin fragment 1, and Ca 2؉ strongly inhibited binding to prothrombin. In Western blot, immunofluorescence, and surface plasmon resonance assays the antibodies bound peptides conjugated to bovine serum albumin that contained either a single Gla or a tandem pair of Gla residues. Binding was maintained when the sequence surrounding the Gla residue(s) was altered. Replacement of Gla with glutamic acid resulted in a complete loss of the epitope. The utility of the antibodies was demonstrated in immunochemical methods for detecting Gla-containing proteins and in the immunopurification of a factor Xa-like protein from tiger snake venom. The amino acid sequences of the Gla domain and portions of the heavy chain of the snake protein were determined.

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Identification of residues in the Gla-domain of human factor IX involved in the binding to conformation specific antibodies

Cited by 7 publications

References 58 publications

Crystal Structure of the Calcium-stabilized Human Factor IX Gla Domain Bound to a Conformation-specific Anti-factor IX Antibody

Crystal Structure of the Calcium-stabilized Human Factor IX Gla Domain Bound to a Conformation-specific Anti-factor IX Antibody

Functional mapping of anti-factor IX inhibitors developed in patients with severe hemophilia B

Identification and Purification of Vitamin K-dependent Proteins and Peptides with Monoclonal Antibodies Specific for γ-Carboxyglutamyl (Gla) Residues

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