C H A P T E R 3 6 , F I G U R E 8

Fibrinogen and polymerizing fibrin monomers. The fibrinogen molecule is a

340,000-Da protein consisting of three pairs of ploypeptide chains: two Aa chains, and two Bp chains, and two y

chains. The A and B designations refer to the two A peptides and two B peptides cleaved from fibrinogen by thrombin

to produce the self-polymerizing fibrin monomer (Fnm), the building block of the fibrin blood clot. The polypeptide

chains are linked together by disulfide bridges between Cy-SH residues of the chains. Only after chemical reduction

of the disulfide bonds are the separate chains of the fibrinogen molecule discernible. Fibrinogen is frequently abbrevi-

ated as (Aa, Bp, -y)2. The 16-residue A (FPA) and 14-residue B (FPB) peptides are at the N-terminal ends of the A

and the B chains, respectively. The central domain, also identified as the E domain, contains portions of all of the six

chains of fibrinogen. The two terminal domains, the D domains, also contain polypeptide sequences from all six

chains.

Phospholipid

molecules

8 0 - 9 0 A

- 7 0 A

P h o s p h o lip id B ila y er

Surface (One side)

C H A P T E R 3 6 , F I G U R E 9

Archetypal activation complex of coagulation:

p ro th ro m b in a se.

Complex formation

precedes rapid proteolysis of prothrombin. The presence of the specific domains and the binding sites associated with

them are responsible for the formation of the complexes between the correct proteins. The A domains of factor Va

provide the interacting sites for both factor Xa and prothrombin, the C domains the sites for binding to the surface.

The Gla domains bind Ca2+ (white dots) and bind factor Xa and prothrombin to the surface. The locations of the vari-

ous sites further orient the molecules optimally with respect to the surface and to each other to give the localized,

large increases in rates of proteolysis. The conversion of the proenzyme form of a proteinase to its catalytically active

form commonly requires proteolysis of a peptide bond that frees a Leu, He, or Val residue from the peptide linkage.

This permits a conformation change within the active proteinase domain that is stabilized by the formation of a salt

bridge between the newly freed residue and Asp102 (chymotrypsin numbering). Proteolysis,

p e r s e

, is not the key ele-

ment in “enabling” of the catalytic apparatus of the proteinase, but rather the conformation that is stabilized by the

salt bridge. The dimensions indicated on the figure are measured distances between fluorescent labels on the proteins

(active sites for factor Xa and meizothrombin) and a fluorophore in the membrane.