Structure–function and regulation of ADAMTS‐13 protease

Abstract

Summary ADAMTS13, a plasma reprolysin-like metalloprotease, cleaves von Willebrand factor (VWF). Severe deficiency of plasma ADAMTS13 activity results in thrombotic thrombocytopenic purpura (TTP), while mild to moderate deficiencies of plasma ADAMTS13 activity are emerging risk factors for developing myocardial and cerebral infarction, preeclampsia, and malignant malaria. Moreover, Adamts13−/− mice develop more severe inflammatory responses, leading to increased ischaemia/perfusion injury and formation of atherosclerosis. Structure-function studies demonstrate that the N-terminal portion of ADAMTS13 (MDTCS) is necessary and sufficient for proteolytic cleavage of VWF under various conditions and attenuation of arterial/venous thrombosis after oxidative injury. The more distal portion of ADAMTS13 (TSP1 2–8 repeats and CUB domains) may function as a disulphide bond reductase to prevent an elongation of ultra large VWF strings on activated endothelial cells and inhibit platelet adhesion/aggregation on collagen surface under flow. Remarkably, the proteolytic cleavage of VWF by ADAMTS13 is accelerated by FVIII and platelets under fluid shear stress. A disruption of the interactions between FVIII (or platelet glycoprotein 1bα) and VWF dramatically impairs ADAMTS13-dependent proteolysis of VWF in vitro and in vivo. These results suggest that FVIII and platelets may be physiological cofactors regulating VWF proteolysis. Finally, the structure-function and autoantibody mapping studies allow us to identify an ADAMTS13 variant with increased specific activity but reduced inhibition by autoantibodies in patients with acquired TTP. Together, these findings provide novel insight into the mechanism of VWF proteolysis and tools for the therapy of acquired TTP and perhaps other arterial thrombotic disorders.

Postpartum TTP-HUS Syndrome: A Rare Autopsy Case Report in a Tertiary Care Hospital.

“…In pregnancy, risk period is near term and during postpartum period. [4] This period also carries profound risk for thrombotic events and other pregnancy associated syndromes like preeclampsia, eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes and low platelets). These conditions may also present with thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, and renal insufficiency, as a result of which it is difficult in making their distinction from HUS-TTP.…”

“…[4] Deficiency or impaired activity of this enzyme leads to TTP.The activity of ADAMTS13 progressively decreases during the course of pregnancy. During pregnancy, there is physiological increase in vWF concentrations .It has been shown that ADAMTS13 activity inversely correlates with plasma von Willebrand factor concentrations.…”

“…The tubules are often atrophic, may show necrosis, and frequently contain hyaline casts and red blood cells. [3,4] …”

ADAMTS13, lucky to have a hydrophobic pocket

“…We and others have shown that T2C may be dispensable or required for binding to native/soluble VWF and endothelium-bound ultra large VWF. 4 Interestingly, more recent studies by kinetic analyses indicate that T2C, particularly the CUB domains, may play a regulatory role by inhibition of ADAMTS13 activity through their potential interaction with the spacer domain (see panel A). This was shown by an approximate twofold increase in proteolytic activity after T2C or 2 CUB domains were deleted or after addition of a monoclonal antibody that bound to the CUB domains.…”

“…This was first described using lipidated peptides based on the receptor sequence called pepducins. 4 Depending on the sequence used, these can act as agonists or…”