Normal Plasmic Cleavage of the γ-Chain Variant of “Fibrinogen Saga” with an Arg–275 to His Substitution

Summary

We have identified a γ-Arg–275 to His substitution in an abnormal fibrinogen designated as “fibrinogen Saga” characterized by impaired fibrin monomer polymerization. By chromatofocusing chromatography, we isolated normal and abnormal fragment D_l populations separately from the plasmic-calcium digests of fibrinogen derived from the propositus, a heterozygote for the abnormality. We found that both normal and abnormal fragment D₁’s were similarly protected from digestion by plasmin in the presence of calcium ions and further degraded to fragments D₂ and D₃ due to cleavage of the γ-chain remnant when calcium ions were replaced by chelating agents. Abnormal fragment D₁ failed to inhibit both thrombin-clotting of normal fibrinogen and polymerization of normal fibrin monomer, while normal D₁ exhibited marked inhibitory activities. In an aberrant peptide comprising residues γ–274–302 isolated by HPLC from the lysyl endopeptidase-digests of abnormal fragment D₁, we identified a His substituting for an Arg at position 2, which corresponds to position 275 of the mutant γ-chain

Keywords

Fibrinogen Saga - ɣ-Arg → His substitution - Dysfunctional fragment D₁ - Calcium protection from plasmin

• References

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