s e c t io n 36.3

Functional Properties and Structures of the Hemostatic System Factors (Proteins)

849

FIGURE 36-5

(Also see color figure.) Motif structures within coagulation proteins.

Common motifs are found in the amino terminal regions of the proteinase

precursor molecules. Shown are the kringle motifs and EG F-like motifs

found in the vitamin K-dependent proteins and in plasminogen.

Fibronectin (types I and II) motifs and “apple” motifs (named from their

two-dimensional representations) are also present but not shown. Some

epidermal growth factor-like domains contain /3-hydroxylated Asp

residues. The cartoon structures for the motifs are derived from

three-dimensional structures determined by x-ray crystallography or by

two-dimensional NM R spectroscopy.

either to the surfaces or, in the case of integral pro-

teins (tissue factor and thrombomodulin), spanning the

cell membrane. Cofactor proteins enhance the specificity

of the reactions and increase the rate of activation of

the proteinase precursor. Cofactor proteins are shown as

bar diagrams in Figure 36-6.Cofactor protein activation

occurs by proteolysis of the precursor forms by throm-

bin and factor Xa. Activation of the cofactor proteins

exposes the binding sites for factor Xa and prothrombin

(factor Va) and, by analogy, factor IXa and factor X

(factor Villa). Sites of cleavage are indicated in the

diagrams in the figure. Binding of factors V and Va and

factors VIII and Villa to the phospholipid membrane is

mediated by the C domains; binding to their respective

proteinases and proteinase precursors is mediated by the

A domains.

Proteinase Inhibitors

Proteinase inhibitors (proteins) that circulate in plasma

inactivate the hemostatic system proteinases after they

have “essentially completed” their proteolyses. With two

exceptions, a

2

-macroglobulin and tissue factor pathway

inhibitor, all of the inhibitors of the procoagulant, an-

ticoagulant, and fibrinolytic proteinases are SERPINS

FIGURE 36-6

(Also see color figure.) Cofactor proteins, factor V and factor V III. Factor V and factor V III coagulant (not the von

Willebrand factor carrier of factor V III) contain six distinct structural domains. The two A domains A i and A

2

at the

N-terminal end of the polypeptide chain are separated from the A

3

domain by a highly glycosylated B domain. The two

C

domains are at the C-terminal end of the molecule. The A domain sequences are homologous to the A domains of

ceruloplasmin. Both factor Va and factor V illa act as catalysts in the activation of prothrombin and factor

X,

respectively. In the color version of this figure, activation sites are indicated by green arrows; inactivation sites by red

arrows. In factor Va, complete inactivation requires cleavage of Arg306.