Contribution of the alpha EC domain to the structure and function of fibrinogen-420.

In addition to the conventional fibrinogen with its alpha, beta, and gamma subunit chains, there is a subclass of fibrinogen molecules, accounting for one percent of the total in human adults, in which both alpha chains have been replaced by extended alpha chains (alpha E) that sport a globular C-terminal domain (alpha EC) comparable to beta C and gamma C. Using nomenclature based on molecular weight, the subclass of alpha E-containing molecules has been named fibrinogen-420 to differentiate it from the better known fibrinogen, now referred to as fibrinogen-340. Review of the events leading to the discovery of fibrinogen-420 in the early 1990s and its subsequent characterization, culminating in the crystal structure of its unique alpha EC domains, highlights special aspects of its evolutionary history, outstanding features of its structure, and the perplexities of its biology. Various working hypotheses that have driven prior investigation are evaluated and practical insights are offered to spur further research into the role of fibrinogen-420.