Abstract
Mature thrombin-activable fibrinolysis inhibitor (TAFIa) is a highly unstable metallocarboxypeptidase that stabilizes blood clots by clipping C-terminal lysine residues from partially degraded fibrin. In accordance with its in vitro antifibrinolytic 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 antifibrinolytic 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 toward a potential heparin-binding site and could explain how heparin stabilizes TAFIa.
Highlights
The removal of this peptide takes place by proteolytic cleavage of a specific Arg-Ala peptide bond at the loop between the pro-domain and the catalytic moiety
TAFIa down-regulates fibrinolysis by removing C-terminal lysine residues from fibrin that has already been partially degraded by plasmin
Describing the significant intrinsic catalytic activity of Thrombin-activable fibrinolysis inhibitor (TAFI) and its potential capability to act in fibrinolysis, a function until recently exclusively assigned to its mature form, TAFIa
Summary
Rived inflammatory peptides [12]. This enzyme is considered an important biomedical target [13]. TAFI shows around 40% sequence identity to several metallocarboxypeptidases of the M14A subfamily (Fig. 1), sharing with them the most important residues implicated in catalysis, zinc binding, and substrate binding [2, 14] It displays carboxypeptidase B (CPB)-like specificity, as mentioned above, it is designed to trim a polymeric natural protein substrate (fibrin) and not peptides like most of the CPB-like enzymes. It was suggested that the instability of the activity of TAFIa is due to intrinsic structural lability of the enzyme [19] This is quite unusual among metallocarboxypeptidases, which are generally very stable enzymes in the mature form [14]. It will help to understand the instability of the mature enzyme and predict its ligands and ligand-binding sites These results reinforce a recent report of one of our groups [20]. Describing the significant intrinsic catalytic activity of TAFI and its potential capability to act in fibrinolysis, a function until recently exclusively assigned to its mature form, TAFIa
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