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

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

Ke, Ke

关键词: blood coagulation;    coagulation factors;    tissue factor;    factor VIIa;    factor X;    membranes;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/44458/Ke_Ke.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Initiation of the coagulation cascade in vivo is mediated by tissue factor (TF), whichfunctions as the cell surface receptor and catalytic cofactor for factor VIIa (FVIIa), as well as themediator for the autoactivation of factor VII (FVII) to FVIIa. Upon vascular injury, TF isexposed to the bloodstream where it comes into contact with FVII(a). The TF/FVIIa complexcan be considered as a two-subunit enzyme: TF is the regulatory subunit; and FVIIa is thecatalytic subunit. FVIIa does have some proteolytic activity by itself; however, association withTF inserted in an appropriate phospholipid bilayer increases its proteolytic activity onmacromolecular substrates many million-fold. The mechanisms by which TF enhances theactivity of FVIIa, and the role of the membrane surface in enhancing catalysis by the TF/FVIIacomplex are yet not fully understood. To elucidate the mechanisms of the cell-surface complexof TF/FVIIa to trigger the initiation phase of the blood clotting, I investigated how amino acidside chain of TF interacted with anionic phospholipids on cell membranes, and how theTF/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 limitedproteolysis 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), inwhich the active site serine residue has been mutated to alanine, an ongoing project is designedto shed light on several unresolved questions regarding FVII activation: 1) which protease playsmajor role in activating FVII during clotting?; 2) what are the influences of various proteincofactors on FVII activation?; and 3) where and how are the basal levels of the circulating FVIIagenerated?