A DOUBLE-HEADED GLY-PRO-ARG-PRO LIGAND MIMICS THE FUNCTIONS OF THE E-DOMAIN OF FIBRIN FOR PROMOTING THE END-TO-END CROSS-LINKING OF GAMMA-CHAIN BY FACTOR XIIIA

The E domain of fibrinogen represents the central region of the protei n that, after the removal of fibrinopeptides from the N-termini of its alpha chains by thrombin, orders the noncovalent assembly of fibrin u nits into a half-staggered array. This structural organization is acco mplished purely through noncovalent binding between the E domain of on e molecule and the distal D domains of two others, The process of asse mbly has a physiologically important up-regulatory effect on the next enzymatic phase of blood coagulation, which is the factor XIIIa-cataly zed end-to-end ligation of the gamma chains at the D domains of the pr otein, Fibrin assembly, as well as the acceleration of the factor XIII a reaction, could be prevented by Gly-Pro-Arg-Pro, a homologue of the natural sequence of amino acids at the N termini of alpha chains in th e E domain, We have now succeeded with a simple double-headed ligand, bis (Gly-Pro-Arg-Pro-amido)polyethylene glycol, in fully replacing the regulatory functions of the large E domains of the native protein.