The tissue factor-factor VII(a) complex in blood coagulation

Initiation of the coagulation cascade in vivo is mediated by tissue factor (TF), which functions as the cell surface receptor and catalytic cofactor for factor VIIa (FVIIa), as well as the mediator for the autoactivation of factor VII (FVII) to FVIIa. Upon vascular injury, TF is exposed to the bloodstream where it comes into contact with FVII(a). The TF/FVIIa complex can be considered as a two-subunit enzyme: TF is the regulatory subunit; and FVIIa is the catalytic subunit. FVIIa does have some proteolytic activity by itself; however, association with TF inserted in an appropriate phospholipid bilayer increases its proteolytic activity on macromolecular substrates many million-fold. The mechanisms by which TF enhances the activity of FVIIa, and the role of the membrane surface in enhancing catalysis by the TF/FVIIa complex are yet not fully understood. To elucidate the mechanisms of the cell-surface complex of TF/FVIIa to trigger the initiation phase of the blood clotting, I investigated how amino acid side chain of TF interacted with anionic phospholipids on cell membranes, and how the TF/FVIIa complex recognized its protein substrates in the context of the membrane. It has been reported that, in vitro, zymogen FVII can be activated to FVIIa via limited proteolysis at a single peptide bond by many proteases, including factor Xa, factor IXa, thrombin, and factor XIIa, as well as FVIIa in complex with TF. By using a FVII mutant (S344A), in which the active site serine residue has been mutated to alanine, an ongoing project is designed to shed light on several unresolved questions regarding FVII activation: 1) which protease plays major role in activating FVII during clotting?; 2) what are the influences of various protein cofactors on FVII activation?; and 3) where and how are the basal levels of the circulating FVIIa generated?

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Ke, Ke

Contributors dc:contributor

• Morrissey, James H.
• Gennis, Robert B.
• Tajkhorshid, Emad
• Chen, Lin-Feng

• blood coagulation
• coagulation factors
• tissue factor
• factor VIIa
• factor X
• membranes

Statement dc:rights

• Copyright 2013 Ke Ke

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/44458

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/44458