The Structure and Function of the αC Domains of Fibrinogen

Publisher Website
Google Scholar
Abstract
Abstract: The αC 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 αC domains suggested that each is made up of a globular and an extended portion. Microcalorimetry confirmed this result and showed that the two αC domains interact intramolecularly. Electron microscopy of fibrinogen with a monoclonal antibody to the αC 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 αC 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 αC domains, indicate that intermolecular interactions between αC domains are important for the enhancement of lateral aggregation during fibrin polymerization. Isolated αC fragments polymerized at neutral pH and interacted with the αC domains of fibrin monomer to influence clot formation. Several dysfibrinogenemias in which there are amino acid substitutions in, or truncations of, the αC domains revealed that these changes can have dramatic effects on polymerization and clot structure. The polymerization of Aα251 recombinant fibrinogen, that contains Aα 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 αC domains in determining the structure and properties of clots.