Generation of a stable thrombin-activatable fibrinolysis inhibitor deletion mutant exerting full carboxypeptidase activity without activation

Journal of Thrombosis and Haemostasis : JTH
X Zhou, P J Declerck

Abstract

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen that can be activated to form activated TAFI (TAFIa) (Ala93-Val401) through removal of the N-terminal activation peptide (Phe1-Arg92). TAFIa is thermally unstable, and the role of the activation peptide in the activity and stability of TAFI zymogen remains unclear. To better understand the role of the activation peptide in the activity and stability of TAFI. We constructed a deletion mutant, TAFI-CIIYQ-∆1-73 , in which the first 73 amino acids of the activation peptide are absent. The intrinsic activity and functional stability were determined with a chromogenic assay. The activation of TAFI-CIIYQ-∆1-73 by TAFI activators was evaluated with western blot analysis. In comparison with TAFI-CIIYQ, the deletion mutant exerted high intrinsic activity ('full' apparent TAFIa activity) without cleavage by TAFI activators. TAFI-CIIYQ-∆1-73 was cleavable by thrombin. However, in the presence of thrombomodulin, the thrombin-mediated cleavage of TAFI-CIIYQ-∆1-73 was not accelerated. TAFI-CIIYQ-∆1-73 showed a similar functional stability profile to that of TAFI-CIIYQ. Full cleavage by thrombin did not affect the apparent carboxypeptidase activity of TAFI-CIIYQ-∆1-73 , but result...Continue Reading

References

Feb 25, 2000·Clinica Chimica Acta; International Journal of Clinical Chemistry·K A SchattemanD F Hendriks
Dec 2, 2006·The Journal of Biological Chemistry·Zuzana ValnickovaJan J Enghild
Dec 8, 2007·Circulation Research·Karlien BuelensAnn Gils
Feb 7, 2008·The Journal of Biological Chemistry·Jonathan H FoleyMichael E Nesheim
Dec 5, 2008·Journal of Thrombosis and Haemostasis : JTH·P F MarxJ C M Meijers
Jul 30, 2014·Journal of Thrombosis and Haemostasis : JTH·T PlugJ C M Meijers

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Citations

Jan 21, 2016·Journal of Thrombosis and Haemostasis : JTH·T Plug, J C M Meijers
Mar 18, 2015·Journal of Thrombosis and Haemostasis : JTH·T Plug, J C M Meijers
May 1, 2021·International Journal of Molecular Sciences·Machteld Sillen, Paul J Declerck

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