Selective loss of fibrinogen clotting in a loop-less thrombin.
The autolysis loop of thrombin comprises nine residues, from Glu146 to Lys149e, five of which (Ala149a-Lys149e) are inserted relative to trypsin and chymotrypsin. Deletion of the insertion Ala149a-Lys149e causes no significant change in the properties of the enzyme, except for a slight enhancement of protein C activation. Deletion of the entire Glu146-Lys149e loop, however, reduces fibrinogen clotting 240-fold, but decreases protein C activation only 2-fold. This loop-less mutant is de facto an exclusive activator of protein C, having lost the primary procoagulant function of thrombin. Because the autolysis loop affects fibrinogen binding, but not protein C activation, it provides a target for new drugs designed to suppress exclusively the procoagulant activity of thrombin.
Dang
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QD
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Sabetta
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M
Di Cera
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E
D001329:Autolysis; D001777:Blood Coagulation; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D011486:Protein C / Q000378:metabolism; D017510:Protein Folding; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000235:genetics / Q000378:metabolism*
D011486:Protein C; D005340:Fibrinogen; D012964:Sodium; D013917:Thrombin