ADAMTS13: Structure and Function

Abstract

ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (VWF), has been shown to have both antithrombotic and anti-inflammatory activities. Severe deficiency of plasma ADAMTS13 activity is a primary cause of thrombotic thrombocytopenic purpura (TTP), a potentially fatal syndrome, but mild to moderate deficiency of plasma ADAMTS13 activity may be associated with increased risk for many other pathologies, including myocardial/cerebral infarction, malignant malaria, preeclampsia, and acute and chronic inflammation. Structure–function analyses demonstrate that N-terminal fragment containing a metalloprotease domain, a disintegrin domain, the first thrombospondin type 1 repeat (TSP1 1), a cysteine-rich domain, and a spacer domain (i.e., MDTCS) appears to be sufficient for recognition and proteolytic cleavage of VWF in vitro and in vivo. The role of more distal C-terminal domains including TSP1 2–8 repeats and CUB (the complement C1r/C1s, Uegf, and Bmp1) domains remains to be determined. Recent studies suggest that TSP12–8 and CUB domains may negatively regulate ADAMTS13 activity. Further investigations of the binding sites of anti-ADAMTS13 autoantibodies from acquired TTP patients may help redesign ADAMTS13 protease for therapeutic use.