University of Wisconsin
School of Medicine and Public Health

Diagrams and graphics created by Dr. Sheehan's lab

Figure 1. Model for tissue factor (TF) dependent blood coagulation. The coagulation cascade is a series of reactions in which the sequential activation of serine proteases amplify the generation of thrombin, which then converts soluble fibrinogen in to an insoluble fibrin clot. The coagulation factors are identified by roman numerals, with a small "a" following the numeral to indicate the activated form. The membrane-bound enzyme complexes of coagulation are indicated by the circles. The initiation phase is triggered by formation of the TF-FVIIa complex. The propagation phase amplifies the response through the FIXa-FVIIIa complex (intrinsic tenase). FX activation by the intrinsic tenase complex is the rate-limiting step for thrombin generation in tissue factor dependent blood coagulation.

Figure 2. Mechanism for heparin inhibition of the intrinsic tenase complex. Factor IXa (pink) and factor VIIIa (blue) are assembled on the phospholipids surface. The domain structures of FIXa (Gla, EGF1, EGF2, and protease) and FVIIIa (A1, A2, and A3-C1-C2) are labeled with putative FVIIIa interactive sites on FIXa (highlighted yellow). Heparin oligosaccharide bound to the C-terminal alpha helix of FIXa is represented with a thick red chain that displaces the FVIIIa A2 domain.

Figure 3. Crystal structure of the Factor IXa protease-EGF2 fragment (1RFN). A ribbon diagram was created with PyMOL. The EGF2 domain is positioned below the protease domain, with the active site oriented upward. The active site S195, and surface residues H92, K126, N129, K132, R165, R170, N178, R233, and R241 are labeled and highlighted with a space filling representation of their respective side chains. The protease heparin-binding exosite is centered near the side chains of R165 and R233.

Figure 4. Homology model of zebrafish factor VII. The three-dimensional structure of zebrafish factor VIIa (Right) was generated by homology modeling (see Materials and Methods) compared with the crystal structure of human factor VIIa (Left) from the soluble tissue factor-factor VIIa complex. rms agreement of the alpha carbon backbone of zebrafish with human factor VIIa is color-coded (blue < 2 Å, yellow = 2-4 Å, red > 4 Å). Sheehan et al PNAS 98(15): 8768-8773.