Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI–Glu555): a cross‐reactive material positive variant defective in factor IX activation
| Autor: | Uri Seligsohn, David Gailani, S Bulvik, John R. Toomey, Taketoshi Ogawa, Jacqueline M. Lane, Ariella Zivelin, Meytal Landau |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Proteases Factor XI Deficiency medicine.medical_treatment Antithrombin III Static Electricity Mutation Missense Factor IX Serine Thrombin medicine Humans Factor XI Binding Sites Protease Chemistry Homozygote Antithrombin Hematology Kinetics Coagulation Biochemistry Protein Binding medicine.drug |
| Zdroj: | Journal of Thrombosis and Haemostasis. 2:1782-1789 |
| ISSN: | 1538-7836 |
| Popis: | During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIa(WT)). When compared with FXIa(WT), FXIa-Glu555 activates factor IX at a greatly reduced rate ( approximately 400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIa(WT) and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable k(cat)s. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2' site and the P2' residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation. |
| Databáze: | OpenAIRE |
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