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Structure of Activated Thrombin-Activatable Fibrinolysis Inhibitor, a Molecular Link between Coagulation and Fibrinolysis

AuthorsSanglas, Laura; Valnickova, Zuzana; Arolas, Joan L. ; Pallarés, Irantzu; Guevara, Tibisay ; Solà, Maria ; Kristensen, Torsten Nygaard; Enghild, Jan J.; Avilés, Francesc X.; Gomis-Rüth, F. Xavier
Thrombin activatable fibrinolysis inhibitor
Issue Date22-Aug-2008
PublisherCell Press
CitationMolecular Cell 31(4): 598-606 (2008)
AbstractThrombin-activatable fibrinolysis inhibitor (TAFI) is a metallocarboxypeptidase (MCP) that links blood coagulation and fibrinolysis. TAFI hampers fibrin-clot lysis and is a pharmacological target for the treatment of thrombotic conditions. TAFI is transformed through removal of its prodomain by thrombin-thrombomodulin into TAFIa, which is intrinsically unstable and has a short half-life in vivo. Here we show that purified bovine TAFI activated in the presence of a proteinaceous inhibitor renders a stable enzyme-inhibitor complex. Its crystal structure reveals that TAFIa conforms to the α/β-hydrolase fold of MCPs and displays two unique flexible loops on the molecular surface, accounting for structural instability and susceptibility to proteolysis. In addition, point mutations reported to enhance protein stability in vivo are mainly located in the first loop and in another surface region, which is a potential heparin-binding site. The protein inhibitor contacts both the TAFIa active site and an exosite, thus contributing to high inhibitory efficiency. © 2008 Elsevier Inc. All rights reserved.
Publisher version (URL)http://dx.doi.org/10.1016/j.molcel.2008.05.031
Identifiersdoi: 10.1016/j.molcel.2008.05.031
issn: 1097-2765
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