Fibrinogen Petoskey, a dysfibrinogenemia characterized by replacement of Arg-A alpha 16 by a histidyl residue. Evidence for thrombin-catalyzed hydrolysis at a histidyl residue.

Inherited abnormal fibrinogens that exhibit altered behavior in one or more of the steps in the conversion of fibrinogen to fibrin should be useful for determining structure-function relationships important in the final stages of blood coagulation. In this work, we show that the inherited dysfibrinogenemia, fibrinogen Petoskey, is due to an Arg --* His replacement at residue 16 in the Aa chain of fibrinogen. This mutation involves the aminoacyl residue that provides the carbonyl portion of the peptide bond cleaved in the thrombin-catalyzed release of fibrinopeptide A from fibrinogen in the conversion of fibrinogen to fibrin. Thrombin treatment of fibrinogen from patients with fibrinogen Petoskey, followed by high performance liquid chromatography, indicated that equal amounts of normal and an abnormal fibrinopeptide A were liberated from the patients’ fibrinogen. This result indicates that the patients studied are heterozygotes with respect to their fibrinogen, which is consistent with the autosomal dominant mode of inheritance observed for their phenotypic prolonged thrombin clotting time. Amino acid analysis and carboxypeptidase Y digestion of the fibrinopeptides established the Arg + His interconversion for fibrinogen Petoskey. Our observation that thrombin catalyzes the hydrolysis of a histidyl peptide bond in the abnormal hrinogen is the first report of a thrombin-catalyzed cleavage of a peptide bond other than at an arginyl or lysyl residue, and suggests that the arginyl residue in fibrinogen can bind to the active site of thrombin with its side chain extended in a conformation similar to that of a histidyl side chain.