Membrane-bound model of the ternary complex between factor VIIa/tissue factor and factor X.

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• The extrinsic complex (EC) initiates blood coagulation.
• Tissue factor (TF), factor VIIa (FVIIa), and factor X (FX) form the EC on cell membranes.
• The lipid-dependent nature of EC formation has hindered structural studies.

Purpose of the Study:

• To develop the first atomic-level model of the membrane-bound EC.
• To elucidate the structural interactions within the EC, considering membrane influence.

Main Methods:

• Combined rigid-body protein-protein docking with nonequilibrium molecular dynamics simulations.
• Incorporated phosphatidylserine/phosphatidylcholine membranes explicitly.
• Generated over 1 million protein-only structures for initial docking.

Main Results:

• Developed the first atomic-level, membrane-bound model of the EC.
• Identified key contact points between FX, TF, and FVIIa.
• FX interacts via its GLA and protease domains; the light chain is solvent-exposed.
• TF exosite binds both FVIIa-GLA and FX-GLA domains, with specific TF residues (K165, K166) mediating these interactions.

Conclusions:

• The TF substrate-binding exosite is critical for EC formation.
• The exosite acts as a pivotal interface linking the GLA domains of FVIIa and FX.
• This model provides new insights into the initiation of the coagulation cascade.