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    Structural model of tissue factor (TF) and TF-factor VIIa complex in a lipid membrane: A combined experimental and computational study

    Journal: J. Colloid Interface Sci., Volume 623, OCT, page 294–305

    Authors: Luchini, Alessandra; Tidemand, Frederik Gronbaek; Araya-Secchi, Raul; Campana, Mario; Cardenas, Marite; Arleth, Lise

    Organizations: Novo Nordisk foundation Interdisciplinary Synergy program; Lundbeck foundation BRAINSTRUCproject; Swedish Research Council; Danscatt

    Keywords: Membrane proteins; Tissue factor; Supported lipid bilayers; Neutron reflectometry; QCM-D; Molecular dynamics simulations; Peptide discs

    Tissue factor (TF) is a membrane protein involved in blood coagulation. TF initiates a cascade of proteolytic reactions, ultimately leading to the formation of a blood clot. The first reaction consists of the binding of the coagulation factor VII and its conversion to the activated form, FVIIa. Here, we combined experimental, i.e. quartz crystal microbalance with dissipation monitoring and neutron reflectometry, and computational, i.e. molecular dynamics (MD) simulation, methods to derive a complete structural model of TF and TF/FVIIa complex in a lipid bilayer. This model shows that the TF transmembrane domain (TMD), and the flexible linker connecting the TMD to the extracellular domain (ECD), define the location of the ECD on the membrane surface. The average orientation of the ECD relative to the bilayer surface is slightly tilted towards the lipid headgroups, a conformation that we suggest is promoted by phosphatidylserine lipids, and favours the binding of FVIIa. On the other hand, the formation of the TF/FVIIa complex induces minor changes in the TF structure, and reduces the conformational freedom of both TF and FVIIA. Altogether we describe the protein-protein and protein-lipid interactions favouring blood coagulation, but also instrumental to the development of new drugs. (C) 2022 Elsevier Inc. All rights reserved.
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