Structure‐function of anticoagulant TIX‐5, the inhibitor of factor Xa‐mediated FV activation
Autor: | Wil F. Kopatz, Cornelis van 't Veer, J. Arnoud Marquart, Joost C. M. Meijers, Tom van der Poll, Mettine H.A. Bos, Priyanka Sharma, Gerry A. F. Nicolaes, Tim J. Schuijt, Tilman M. Hackeng, Daniëlle Kruijswijk, Anja Maag |
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Přispěvatelé: | Center of Experimental and Molecular Medicine, Graduate School, ACS - Pulmonary hypertension & thrombosis, Experimental Vascular Medicine, Vascular Medicine, RS: Carim - B01 Blood proteins & engineering, Biochemie |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
factor Xa
Phospholipid Hemorrhage 030204 cardiovascular system & hematology Thromboplastin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Thrombin Prothrombinase medicine Humans Blood Coagulation factor V biology Chemistry HAEMOSTASIS anticoagulant Factor V Anticoagulants Hematology Original Articles Mechanism of action Coagulation Factor Va Phospholipid Binding Biophysics biology.protein Original Article Prothrombin medicine.symptom Alpha helix medicine.drug Factor Xa Inhibitors |
Zdroj: | Journal of Thrombosis and Haemostasis Journal of thrombosis and haemostasis, 19(7), 1697-1708. Wiley-Blackwell Journal of Thrombosis and Haemostasis, 19(7), 1697-1708. WILEY Journal of Thrombosis and Haemostasis, 19(7), 1697-1708. Wiley |
ISSN: | 1538-7836 1538-7933 |
Popis: | Background The prothrombinase complex consists of factors Xa (FXa) and Va (FVa) on an anionic phospholipid surface and converts prothrombin into thrombin. Both coagulation factors require activation before complex assembly. We recently identified TIX-5, a unique anticoagulant tick protein that specifically inhibits FXa-mediated activation of FV. Because TIX-5 inhibited thrombin generation in blood plasma, it was concluded that FV activation by FXa contributes importantly to coagulation.Objective We aimed to unravel the structure-function relationships of TIX-5.Method We used a structure model generated based on homology with the allergen Der F7.Results Tick inhibitor of factor Xa toward FV was predicted to consist of a single rod formed by several beta sheets wrapped around a central C-terminal alpha helix. By mutagenesis we could show that two hydrophobic loops at one end of the rod mediate the phospholipid binding of TIX-5. On the other end of the rod an FV interaction region was identified on one side, whereas on the other side an EGK sequence was identified that could potentially form a pseudosubstrate of FXa. All three interaction sites were important for the anticoagulant properties of TIX-5 in a tissue factor-initiated thrombin generation assay as well as in the inhibition of FV activation by FXa in a purified system.Conclusion The structure-function properties of TIX-5 are in perfect agreement with a protein that inhibits the FXa-mediated activation on a phospholipid surface. The present elucidation of the mechanism of action of TIX-5 will aid in deciphering the processes involved in the initiation phase of blood coagulation. |
Databáze: | OpenAIRE |
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