NDLI: Kinetics of Activated Thrombin-activatable Fibrinolysis Inhibitor (TAFIa)-catalyzed Cleavage of C-terminal Lysine Residues of Fibrin Degradation Products and Removal of Plasminogen-binding Sites*

Content Provider	PubMed Central
Author	Foley, Jonathan H. Cook, Paul F. Nesheim, Michael E.
Copyright Year	2011
Abstract	Partial digestion of fibrin by plasmin exposes C-terminal lysine residues, which comprise new binding sites for both plasminogen and tissue-type plasminogen activator (tPA). This binding increases the catalytic efficiency of plasminogen activation by 3000-fold compared with tPA alone. The activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis by removing these residues, which causes a 97% reduction in tPA catalytic efficiency. The aim of this study was to determine the kinetics of TAFIa-catalyzed lysine cleavage from fibrin degradation products and the kinetics of loss of plasminogen-binding sites. We show that the kcat and Km of Glu1-plasminogen (Glu-Pg)-binding site removal are 2.34 s−1 and 142.6 nm, respectively, implying a catalytic efficiency of 16.21 μm −1 s−1. The corresponding values of Lys77/Lys78-plasminogen (Lys-Pg)-binding site removal are 0.89 s−1 and 96 nm implying a catalytic efficiency of 9.23 μm −1 s−1. These catalytic efficiencies of plasminogen-binding site removal by TAFIa are the highest of any TAFIa-catalyzed reaction with a biological substrate reported to date and suggest that plasmin-modified fibrin is a primary physiological substrate for TAFIa. We also show that the catalytic efficiency of cleavage of all C-terminal lysine residues, whether they are involved in plasminogen binding or not, is 1.10 μm −1 s−1. Interestingly, this value increases to 3.85 μm −1 s−1 in the presence of Glu-Pg. These changes are due to a decrease in Km . This suggests that an interaction between TAFIa and plasminogen comprises a component of the reaction mechanism, the plausibility of which was established by showing that TAFIa binds both Glu-Pg and Lys-Pg.
Related Links	http://dx.doi.org/10.1074/jbc.m110.215061
Ending Page	19286
Page Count	7
Starting Page	19280
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	22
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-06-03
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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