C H A P T E R 3 6 , F IG U R E 1 0

Activation of prothrombin. Prothrombin is cleaved by factor Xa at two residues,

Arg284 and Arg320. The order of cleavage produces different products. If the first cleavage is at Arg284, it produces two

products: prothrombin fragmentl-2 (residues 1-284, yellow bar) and prethrombin 2 (residues 285-579, gray bar),

each of which represents approximately one-half of the prothrombin molecule. When Arg320 is cleaved first, the inter-

mediate product meizothrombin is formed. Meizothrombin contains the entire sequence of the prothrombin molecule;

the two halves are held together by a single disulfide bond (CyS283 to Cys439). In the absence of factor Va, the rate

constants for cleavage of the two bonds are essentially the same. In the presence of factor Va and phospholipids,

Arg320 is cleaved first. Meizothrombin is detectable in reaction mixtures, but its rapid cleavage produces prothrombin

fragment 1-2 and a-thrombin. Motifs and domains are color coded as follows: Gla domain (blue), kringle domains

(orange), EGF-like domain (magenta), activation peptide (yellow), and proteinase domain (green). Light chains are

indicated in dark gray, heavy chains in light gray. Regions connecting the motifs are black.

C H A P T E R 3 6 , F I G U R E 11

Tissue factor-factor Vila complex. The three-dimensional structure of the complex

of factor Vila and tissue factor (minus the transmembrane polypeptide domain of the tissue factor) in the absence of

membrane surface. It is approximately 115Â in length and has a diameter of 40-50Â. Factor Vila shows its four dis-

tinct domains: the Gla domain, two EGF-like domains, and the proteinase domain. Tissue factor contacts factor Vila

via the interface between the two “fibronectin type Ill-like” domains. All four domains of factor Vila appear to be

involved in the interaction between tissue factor and factor Vila. The Gla domain of factor Vila is folded very similar-

ly to the Gla domain of prothrombin (Gla domain of prothrombin fragment 1). Activation of factor VII can be cat-

alyzed by thrombin, factor Xa, factor Vila and factor Xlla—all by cleavage at ArgI52-Ile153. Secondary structures are

shown in the center diagram; two views of the close interactions between TF and factor Vila are shown in the two

diagrams at each side.