Structure-function of anticoagulant TIX-5, the inhibitor of factor Xa-mediated FV activation.
Research article published in Journal of thrombosis and haemostasis : JTH (2021)
Abstract
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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
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.
Warum dies für die Hirudotherapie relevant ist
Diese Studie untersuchte die Struktur-Funktions-Beziehungen von TIX-5, einem aus Zecken stammenden antikoagulatorischen Protein, das spezifisch die FXa-vermittelte Aktivierung von Faktor V hemmt – einen Schlüsselschritt bei der Prothrombinase-Assemblierung und Thrombingenerierung. Mittels Homologiemodellierung und Mutagenese identifizierten die Forschenden drei funktionelle Interaktionsstellen – Phospholipid-bindende hydrophobe Schleifen, eine FV-Interaktionsregion und eine potenzielle FXa-Pseudosubstrat-EGK-Sequenz –, die alle für die antikoagulatorische Aktivität entscheidend sind. Obwohl TIX-5 ein Antikoagulans eines blutsaugenden Arthropoden ist, stammt es von Zecken und nicht von Blutegeln, und das Abstract erwähnt weder Blutegel, Hirudotherapie noch aus Blutegeln stammende Moleküle. Die Relevanz für das Fachgebiet von ASH beschränkt sich auf den allgemeinen thematischen Kontext von Antikoagulanzien hämatophager Invertebraten, ohne direkten Bezug zu Blutegeln.
Zitation
Structure-function of anticoagulant TIX-5, the inhibitor of factor Xa-mediated FV activation.
Maag et al. · Journal of thrombosis and haemostasis : JTH, 2021
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