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Thrombin Activatable Fibrinolysis inhibitor (TAFI)

Laura Sanglas Crespi

Thrombin Activatable Fibrinolysis inhibitor, (TAFI), belongs to the family of metallocarboxypeptidases and circulates in plasma as a 60 kDa pro-form. It is a glycoprotein with majority of its N-linked carbohydrates mainly attached to the prodomain, which can be released by proteolysis of the Arg92-Ala93 peptide bond, generating the mature form, TAFIa. The activity of TAFIa, although short-lived, plays a role in fibrinolysis/coagulation by the removal of carboxy-terminal lysine residues from newly formed fibrin clots. Elimination of these lysine residues abrogates the t-PA mediated plasminogen activation, resulting in a decreased rate of plasmin generation, down regulation of fibrinolysis and stabilization of the fibrin clot.

Interestingly, unlike other pro-forms (zymogens), TAFI displays a stable and significant intrinsic activity, capable of cleaving large substrates. Recently the crystal structure of this protein has been solved, revealing that a significant access to the active site exist, suggesting that TAFI activity might complement the activity of TAFIa. Our ongoing research project is focused on gaining an in-depth understanding of this flexible access, trying to understand its regulation and function.

Although the complete pathophysiological role of TAFI is yet to be clearly defined, its role in fibrinolysis might prove instrumental in the development of therapeutic agents used to treat bleeding and thrombotic disorders.

Right: A superposition of the crystal structures of bovine TAFI (green) and porcine carboxypeptidase B (purple).  The difference in the pro-domain positions is obvious. The TAFI prodomain is rotated 12a in respect to the position of the prodomain in proCPB.
October 24 2008, The Journal of Biological Chemistry, 283, 29416-29423.