TY - JOUR

T1 - Structural model of tissue factor (TF) and TF-factor VIIa complex in a lipid membrane

T2 - A combined experimental and computational study

AU - Luchini, Alessandra

AU - Tidemand, Frederik Gronbaek

AU - Araya-Secchi, Raul

AU - Campana, Mario

AU - Cárdenas, Marité

AU - Arleth, Lise

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Membrane proteins

KW - Tissue factor

KW - Supported lipid bilayers

KW - Neutron reflectometry

KW - QCM-D

KW - Molecular dynamics simulations

KW - Peptide discs

KW - BLOOD-COAGULATION FACTOR

KW - STRUCTURE-BASED DESIGN

KW - PROCOAGULANT ACTIVITY

KW - ACTIVE-SITE

KW - CRYSTAL-STRUCTURE

KW - GLA-DOMAIN

KW - SURFACE

KW - INHIBITORS

KW - BINDING

KW - SIMULATIONS

U2 - 10.1016/j.jcis.2022.04.147

DO - 10.1016/j.jcis.2022.04.147

M3 - Journal article

C2 - 35594588

VL - 623

SP - 294

EP - 305

JO - Journal of Colloid and Interface Science

JF - Journal of Colloid and Interface Science

SN - 0021-9797

ER -