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The crystal structure of TAFI provides the structural basis for its intrinsic activity and the short half-life of TAFIa

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  • Kanchan Anand, Denmark
  • Irantzu Pallares, Denmark
  • Zuzana Valnickova
  • Trine Christensen, Denmark
  • Josep Vendrell, Denmark
  • K Ulrich Wendt, Denmark
  • Herman A Schreuder, Denmark
  • Jan J Enghild
  • Francesc X Avilés, Denmark
Mature thrombin activatable fibrinolysis inhibitor (TAFIa) is a highly unstable metallocarboxypeptidase which stabilizes blood clots by clipping C-terminal lysine residues from partially degraded fibrin. In accordance with its in vitro anti-fibrinolytic activity, animal studies have reported that inhibition of mature TAFI aids in the prevention of thrombosis. The level of TAFI activity is stringently regulated through (i) controlled proteolytic truncation of the zymogen (TAFI), generating the mature enzyme, TAFIa and (ii) the short half-life of TAFIa. TAFI itself exhibits an intrinsic enzymatic activity, which is likely required to provide a baseline level of anti-fibrinolytic activity. The novel crystal structure presented here reveals that the active site of TAFI is accessible, providing the structural explanation for the its intrinsic activity. It also supports the notion that an "instability region" exists, in agreement with site directed mutagenesis studies. Sulfate ions, bound to this region point towards a potential heparin-binding site and could explain how heparin stabilizes TAFIa.
Original languageEnglish
JournalJournal of Biological Chemistry
Publication statusPublished - 2008

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