Fib420: a normal human variant of fibrinogen with two extended alpha chains.

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RESUMO

In fibrinogen, alpha E chains form a subpopulation of alpha subunits that are distinguished by a carboxyl extension homologous to the C termini of the other two constituent chains: beta and gamma. The molecular mass of alpha E is > 50% greater than that of the common alpha subunit, due in part to an extra 236 amino acids. These residues are encoded by exon VI, a recently discovered extension of the fibrinogen alpha gene. Additional mass is contributed by posttranslational processing, including N-glycosylation, which, based on experiments with the inhibitor tunicamycin, was found to account in large measure for alpha E migration on SDS/PAGE at approximately 110 kDa rather than at its calculated mass of 92,843 Da. An antibody specific for the exon VI-encoded domain of alpha E (anti-VI) and capable of recognizing alpha E-containing fibrinogen in both native and denatured form was generated using a recombinant protein as immunogen. Its use in Western blot analysis of fractions of normal human blood (plasma and preparations of fibrinogen) revealed a single, sharp, alpha E-containing band migrating behind the position of the broad, predominant fibrinogen band, (alpha beta gamma)2. Designation of the upper band as Fib420, an approximately 420-kDa homodimer of the formula (alpha E beta gamma)2, is based on the overwhelming proportion of alpha E subunits (> 80% of the total alpha chains) found in anti-VI-immunoprecipitable material from hepatoma cell medium. Several lines of evidence suggest that the alpha E subunit, alone or incorporated into fibrinogen, is more stable than the common alpha chain, a feature of potential clinical importance.

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