Domain Organization of Tissue Factor, Factor VIIa and TFPI

Tissue factor (TF) and factor VIIa (FVIIa) are multidomain proteins. TF, the triggering agent of the blood clotting system, is a member of the class 2 cytokine receptor superfamily. The extracellular portion of TF is composed of two fibronectin type III domains (F3), which are themselves a variation of the immunoglobulin fold. This is followed by a membrane spanning domain and a short cytoplasmic tail on the C-terminus.

FVIIa is the ligand for TF, and the resulting TF:VIIa complex is the first enzyme in the clotting cascade. FVIIa contains an N-terminal domain that is rich in the modified amino acid, gamma-carboxyglutamic acid (the Gla domain; indicated in the figure above by the Greek letter, gamma). The Gla domain confers the ability to bind, in a reversible and calcium-dependent manner, to membranes containing negatively charged phospholipids. Next is the aromatic or hydrophobic stack (indicated by the small yellow circle), followed by two epidermal growth factor-like domains (EGF domains; indicated by the letters "EG" in the figure). Last is the serine protease domain, which is structurally related to trypsin and chymotrypsin. The major protein substrates for the TF:VIIa complex, factors IX and X (FIX and FX) have the same domain structure as factor VII.

A key plasma inhibitor of the TF:VIIa complex is tissue factor pathway inhibitor (TFPI; see figure above). TFPI is composed of three Kunitz-type domains (K1-K3), which are homologous to bovine pancreatic trypsin inhibitor (BPTI). The first Kunitz domain binds to the active site of FVIIa, while the second Kunitz domain binds to the active site of FXa. The function of the third Kunitz domain is unknown. The C-terminal domain (represented by "C" in the above figure) can bind to cell-surface proteoglycans and also to the low density lipoprotein receptor-related protein (LRP). TFPI inhibits both FXa and FVIIa (when the latter is bound to tissue factor). Ultimately, this results in the formation of an inhibited tetramolecular complex on the cell surface, composed of TF, FVIIa, FXa and TFPI.