Prog Mol Biol Transl Sci 2011 Jan 01;99:105-44. doi: 10.1016/B978-0-12-385504-6.00003-8.

Structure and proteolytic properties of ADAMTS13, a metalloprotease involved in the pathogenesis of thrombotic microangiopathies.

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ADAMTS13 is a 190-kDa zinc protease encoded by a gene located on chromosome 9q34. This protease specifically hydrolyzes von Willebrand factor (VWF) multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains, including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1) repeats, a cysteine-rich domain, a spacer domain, and two CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein) domains. ADAMTS13 cleaves a single peptide bond (Tyr(1605)-Met(1606)) in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultralarge VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs). In this chapter, we (a) discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, (b) address the ongoing controversies, and (c) indicate the direction of future investigations.

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Genes referenced: LOC100887844 LOC582189 LOC591618 LOC752022 LOC752081 LOC756768 pus1 sema5bl