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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
Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark.
Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark.
Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark.
ISIS-STFC, Rutherford Appleton Laboratory, Chilton, Oxon OX11 0QX, United Kingdom.
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2022 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 623, p. 294-305, article id S0021-9797(22)00724-XArticle in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 623, p. 294-305, article id S0021-9797(22)00724-X
Keywords [en]
Membrane proteins, Molecular dynamics simulations, Neutron reflectometry, Peptide discs, QCM-D, Supported lipid bilayers, Tissue factor
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URN: urn:nbn:se:mau:diva-52207DOI: 10.1016/j.jcis.2022.04.147ISI: 000829956000007PubMedID: 35594588Scopus ID: 2-s2.0-85130078544OAI: oai:DiVA.org:mau-52207DiVA, id: diva2:1666084
Available from: 2022-06-08 Created: 2022-06-08 Last updated: 2024-02-05Bibliographically approved

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Cárdenas, Marité

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