The Story of the Fibrin(ogen) αC-Domains: Evolution of Our View on Their Structure and Interactions

Although much has been established concerning the overall structure and function of fibrinogen, much less has been known about its two alpha C regions, each consisting of an alpha C-connector and an alpha C-domain, but new information has been accumulating. This review summarizes the state of our current knowledge of the structure and interactions of fibrinogen's alpha C regions. A series of studies with isolated alpha C regions and their fragments demonstrated that the alpha C-domain forms compact ordered structures consisting of N- and C-terminal subdomains including beta sheets and suggested that the alpha C-connector has a poly(L-proline) type II structure. Functionally, the alpha C-domains interact intramolecularly with each other and with the central region of the molecule, first demonstrated by electron microscopy and then quantified by optical trap force spectroscopy. Upon conversion of fibrinogen into fibrin, the alpha C-domains switch from intra- to intermolecular interactions to form ordered alpha C polymers. The formation of alpha C polymers occurs mainly through the homophilic interaction between the N-terminal subdomains; interaction between the C-terminal subdomains and the alpha C-connectors also contributes to this process. Considerable evidence supports the idea that the alpha C-regions accelerate fibrin polymerization and affect the final structure of fibrin clots. The interactions between alpha C-regions are important for the mechanical properties of clots, increasing their stiffness and extensibility. Conversion of fibrinogen into fibrin results in exposure of multiple binding sites in its alpha C regions, providing interaction of fibrin with different proteins and cell types during hemostasis and wound healing. This heretofore mysterious part of the fibrinogen molecule is finally giving up its secrets.

Automated summary

This review summarizes the current understanding of the structure and interactions of fibrinogen's alpha C regions. The alpha C-domain and alpha C-connector play important roles in fibrinogen conversion and clot mechanics, as well as interaction with other proteins during hemostasis and wound healing.