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

Laura Sanglas, Zuzana Valnickova, Joan L. Arolas, Irantzu Pallarés, Tibisay Guevara, Maria Solà, Torsten Kristensen, Jan J. Enghild, Francesc X. Aviles, F. Xavier Gomis-Rüth

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

Thrombin-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.
Original languageEnglish
Pages (from-to)598-606
JournalMolecular Cell
Volume31
Issue number4
DOIs
Publication statusPublished - 22 Aug 2008

Keywords

  • PROTEIN

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