The structure and function of the alpha C domains of fibrinogen.

Abstract

The alpha C domains have been localized on fibrinogen and fibrin. Several model systems have been developed to study their functions. Analysis of the amino acid sequence of the alpha C domains suggested that each is made up of a globular and an extended portion. Microcalorimetry confirmed this result and showed that the two alpha C domains interact intramolecularly. Electron microscopy of fibrinogen with a monoclonal antibody to the alpha C domains demonstrated that these regions normally interact with the central portion of the molecule. In the conversion from fibrinogen to fibrin there is a large scale conformational change, such that the alpha C domains dissociate from the central region and are available for intermolecular interaction. Experiments with highly purified and well characterized fragment X monomer, missing either one or both of the alpha C domains, indicate that intermolecular interactions between alpha C domains are important for the enhancement of lateral aggregation during fibrin polymerization. Isolated alpha C fragments polymerized at neutral pH and interacted with the alpha C domains of fibrin monomer to influence clot formation. Several dysfibrinogenemias in which there are amino acid substitutions in, or truncations of, the alpha C domains revealed that these changes can have dramatic effects on polymerization and clot structure. The polymerization of A alpha 251 recombinant fibrinogen, that contains A alpha chains truncated at residue 251, was altered, as were the mechanical properties and the rate of fibrinolysis of the clots. Altogether, these results help to define the role of the alpha C domains in determining the structure and properties of clots.