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.
Resumen
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.
Por qué esto importa para la hirudoterapia
Este estudio examinó las relaciones estructura-función de TIX-5, una proteína anticoagulante derivada de garrapata que inhibe específicamente la activación del factor V mediada por FXa, un paso clave en el ensamblaje de la protrombinasa y la generación de trombina. Mediante modelado por homología y mutagénesis, los investigadores identificaron tres sitios funcionales de interacción: bucles hidrofóbicos de unión a fosfolípidos, una región de interacción con FV y una secuencia EGK pseudosustrato potencial para FXa, todos ellos críticos para la actividad anticoagulante. Aunque TIX-5 es un anticoagulante de un artrópodo hematófago, procede de garrapatas, no de sanguijuelas, y el resumen no menciona sanguijuelas, hirudoterapia ni moléculas derivadas de sanguijuelas. La relevancia para el dominio de la ASH se limita al contexto temático general de los anticoagulantes de invertebrados hematófagos, sin conexión directa alguna con la sanguijuela.
Citación
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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Añadido a la biblioteca ASH: May 28, 2026 · Última actualización del sitio: 18 de junio de 2026