Lancellotti S , Basso M , De Cristofaro R .

	Figure 2. Schematic diagram of ADAM, ADAMTS and ADAMTS13 structure. The structural domains are indicated: signal peptide (S), propeptide (P), metalloprotease (M) (location of zinc-binding motif shown in red), disintegrin domain (Dis), first thrombospondin type 1 (TSP1) repeat (1), cysteine-rich domain (Cys-R), spacer domain (Spa), the second to eighth TSP1 repeats(2) through (8) and two CUB domains (C1 and C2). The metalloprotease domain is the catalytic center that cleaves von Willebrand factor (VWF). The proximal carboxyl-terminal domains from Dis to Spa interact with the A2 domain of VWF. More distal carboxyl-terminal domains (TSP1 2–8) interact with VWF under fluid shear stress. EGF indicates epidermal growth factor-like repeat and TM, transmembrane domain.
	Figure 3. The zinc metalloproteinases of the zincin type that have the minimal catalytic zinc-binding motif containing two histidine residues flanking the catalytic glutamate, HEXXH, comprise three superfamilies: the gluzincins, the aspzincins and the metzincins. Within the metzincins, the major families are the matrixins or matrix metalloproteinases (MMPs), the reprolysins (also known as adamalysins, which includes some ADAM (a disintegrin and metalloproteinase) and ADAMTs (ADAMs with thrombospondin repeats proteins) and the astacins. Metzincins have an HEXXHXXGXXHZ…M motif with three histidine residues binding the zinc ion and an invariant methionine turn in the active site that generates the name metzincins. X represents any amino acid residue and Z indicates a subfamily specific conserved residue, which is D for both ADAM and ADAMTS members. (Inset) Homology modeling of the metalloproteinase (M) domain of ADAMTS-13. The structure was generated using the program RasMol vs. 2.7.5. The structure of the polypeptide chain 80–290, corresponding to the M-domain of ADAMTS13 was modeled by homology on the crystallographic structure of ADAMTS4 solved at 2.80 Å (PDB entry code: 2RJP). Zinc ion (green) is shown together with the three catalytic His-residues. The “Met-turn” typical of the metzincin family is also indicated.
	Figure 4. Pathogenesis of TMA caused by ADAMTS13 deficiency. A) Von Willebrand factor (VWF) multimers, produced and stored in the Weibel-Palade bodies of the endothelial cells, are secreted and adhere to endothelial cell membranes via GpIbα and P-selectin. Platelets adhere to VWF multimers through platelet membrane glycoprotein GPIbα. In flowing blood under high shear stress, VWF in the platelet-rich thrombus is in a stretched conformation and is trimmed by ADAMTS13, which limits thrombus growth. B) If ADAMTS13 is absent or inhibited by autoantibodies, VWF-dependent platelet accumulation is uncontrolled and may cause microvascular thrombosis, formation of schistocytes and, ultimately, TMA.
	Figure 5. Linear map of the location of ADAMTS13 mutations found in patients with congenital thrombotic thrombocytopenic purpura (TTP) [Upshaw-Schulman syndrome (USS)]. The missense mutations, nonsense mutations (red) and single nucleotide polymorphisms (SNPs) (green) are shown above the domain structure of ADAMTS13. The mutations that result in alternative splicing of ADAMTS13 mRNA or frameshifts are listed under the domain structure of ADAMTS13. S indicates the signal peptide; P, propeptide; M, metalloprotease (location of zinc-binding motif shown in red); Dis, disintegrin domain; 1, first thrombospondin type 1 (TSP1) repeat; Cys-R, cysteine-rich domain; Spa, spacer domain; 2 through 8, the second to eighth TSP1 repeats; C1 and C2, two CUB domains (for complement C1r/C1s, Uegf, Bmp1 domain) §p.[C322G (+) T323R (+) F324L].

Ai, The proximal carboxyl-terminal domains of ADAMTS13 determine substrate specificity and are all required for cleavage of von Willebrand factor. 2005, Pubmed

Ai, The proximal carboxyl-terminal domains of ADAMTS13 determine substrate specificity and are all required for cleavage of von Willebrand factor. 2005, Pubmed
Akiyama, ADAMTS13 P475S polymorphism causes a lowered enzymatic activity and urea lability in vitro. 2008, Pubmed
Akiyama, Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor. 2009, Pubmed
Akiyama, Crystal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism. 2013, Pubmed
Antoine, ADAMTS13 gene defects in two brothers with constitutional thrombotic thrombocytopenic purpura and normalization of von Willebrand factor-cleaving protease activity by recombinant human ADAMTS13. 2003, Pubmed
Asada, Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. 1985, Pubmed
Assink, Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency. 2003, Pubmed
Auton, Conformational stability and domain unfolding of the Von Willebrand factor A domains. 2007, Pubmed
Banno, Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. 2006, Pubmed
Bernardo, Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. 2004, Pubmed
Bestetti, ADAMTS 13 genotype and vWF protease activity in an Italian family with TTP. 2003, Pubmed
Bode, Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'. 1993, Pubmed
Bode, Structural properties of matrix metalloproteinases. 1999, Pubmed
Borgi, Congenital Thrombotic Thrombocytopenic Purpura: Atypical Presentation and New ADAMTS 13 Mutation in a Tunisian Child. 2013, Pubmed
Bork, The CUB domain. A widespread module in developmentally regulated proteins. 1993, Pubmed
Cal, Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. 2002, Pubmed
Camilleri, Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. 2008, Pubmed
Chauhan, ADAMTS13: a new link between thrombosis and inflammation. 2008, Pubmed
Chen, Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. 2010, Pubmed
Chung, Processing of von Willebrand factor by ADAMTS-13. 2002, Pubmed
Colige, Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. 1999, Pubmed
Coppo, Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. 2004, Pubmed
Crawley, Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. 2011, Pubmed
Dagoneau, ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. 2004, Pubmed
De Cristofaro, Role of chloride ions in modulation of the interaction between von Willebrand factor and ADAMTS-13. 2005, Pubmed
De Filippis, Oxidation of Met1606 in von Willebrand factor is a risk factor for thrombotic and septic complications in chronic renal failure. 2012, Pubmed
Di Stasio, The effect of shear stress on protein conformation: Physical forces operating on biochemical systems: The case of von Willebrand factor. 2010, Pubmed
Di Stasio, Kinetic study of von Willebrand factor self-aggregation induced by ristocetin. 2009, Pubmed
Donadelli, In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura. 2006, Pubmed
Dong, Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. 2005, Pubmed
Dong, ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. 2002, Pubmed
Dong, Evolution of ADAMTS13 antibodies in a fatal case of thrombotic thrombocytopenic purpura. 2008, Pubmed
Favaloro, Investigations from external quality assurance programs reveal a high degree of variation in the laboratory identification of coagulation factor inhibitors. 2009, Pubmed
Ferrari, IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura. 2009, Pubmed
Frankel, Von Willebrand factor, type 2 diabetes mellitus, and risk of cardiovascular disease: the framingham offspring study. 2008, Pubmed
Fujikawa, Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. 2001, Pubmed
Fujimura, Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients. 2009, Pubmed
Furlan, von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. 1998, Pubmed
Furlan, Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. 1996, Pubmed
Garagiola, Nonsense-mediated mRNA decay in the ADAMTS13 gene caused by a 29-nucleotide deletion. 2008, Pubmed
George, Clinical practice. Thrombotic thrombocytopenic purpura. 2006, Pubmed
Gerritsen, Partial amino acid sequence of purified von Willebrand factor-cleaving protease. 2001, Pubmed
Hanson, Plasma levels of von Willebrand factor in the etiologic subtypes of ischemic stroke. 2011, Pubmed
Hommais, Molecular characterization of four ADAMTS13 mutations responsible for congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). 2007, Pubmed
Hosler, Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. 2003, Pubmed
Hulstein, A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. 2005, Pubmed
Hurskainen, ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family. 1999, Pubmed
Jang, Frequency of Pro475Ser polymorphism of ADAMTS13 gene and its association with ADAMTS-13 activity in the Korean population. 2008, Pubmed
Kentouche, Remission of thrombotic thrombocytopenic purpura in a patient with compound heterozygous deficiency of von Willebrand factor-cleaving protease by infusion of solvent/detergent plasma. 2002, Pubmed
Klaus, Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. 2004, Pubmed
Kokame, Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. 2002, Pubmed
Kokame, Inherited and de novo mutations of ADAMTS13 in a patient with Upshaw-Schulman syndrome. 2008, Pubmed
Lancellotti, Oxidized von Willebrand factor is efficiently cleaved by serine proteases from primary granules of leukocytes: divergence from ADAMTS-13. 2011, Pubmed
Lancellotti, Formation of methionine sulfoxide by peroxynitrite at position 1606 of von Willebrand factor inhibits its cleavage by ADAMTS-13: A new prothrombotic mechanism in diseases associated with oxidative stress. 2010, Pubmed
Levy, Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. 2001, Pubmed
Licht, Two novel ADAMTS13 gene mutations in thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). 2004, Pubmed
Liu, [Identification of two novel mutations in ADAMTS13 gene in a patient with hereditary thrombotic thrombocytopenic purpura]. 2005, Pubmed
Liu, Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. 2005, Pubmed
López, Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells. 2004, Pubmed
Majerus, Binding of ADAMTS13 to von Willebrand factor. 2005, Pubmed
Manea, ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura. 2007, Pubmed
Mannucci, Thrombotic thromboytopenic purpura: another example of immunomediated thrombosis. 2006, Pubmed
Mannucci, Patterns of changes of anti-ADAMTS13 after plasma exchange. 2006, Pubmed
Matsumoto, Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. 2004, Pubmed
McLeod, Thrombotic microangiopathies in bone marrow and organ transplant patients. 2002, Pubmed
Meyer, A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13. 2008, Pubmed
Moake, Thrombotic microangiopathies. 2002, Pubmed
Moake, Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. 1982, Pubmed
Motto, Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice. 2005, Pubmed
Niiya, Increased ADAMTS-13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. 2006, Pubmed
Nishio, Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. 2004, Pubmed
Nolasco, Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers. 2005, Pubmed
Noris, Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. 2005, Pubmed
Oggianu, The oxidative modification of von Willebrand factor is associated with thrombotic angiopathies in diabetes mellitus. 2013, Pubmed
Ono, Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. 2006, Pubmed
Padilla, P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. 2004, Pubmed
Palla, The first deletion mutation in the TSP1-6 repeat domain of ADAMTS13 in a family with inherited thrombotic thrombocytopenic purpura. 2009, Pubmed
Pimanda, Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. 2004, Pubmed
Plaimauer, Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). 2002, Pubmed
Plaimauer, Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. 2006, Pubmed
Raife, Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. 2009, Pubmed
Rawlings, Evolutionary families of metallopeptidases. 1995, Pubmed
Rieger, ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. 2005, Pubmed
Ruggenenti, Thrombotic microangiopathies. 1991, Pubmed
Ruggeri, The complex multimeric composition of factor VIII/von Willebrand factor. 1981, Pubmed
Sadler, von Willebrand factor. 1991, Pubmed
Sadler, Recent advances in thrombotic thrombocytopenic purpura. 2004, Pubmed
Sadler, Biochemistry and genetics of von Willebrand factor. 1998, Pubmed
Saito, Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. 2000, Pubmed
Savasan, ADAMTS13 gene mutation in congenital thrombotic thrombocytopenic purpura with previously reported normal VWF cleaving protease activity. 2003, Pubmed
Scaglione, The type 2B p.R1306W natural mutation of von Willebrand factor dramatically enhances the multimer sensitivity to shear stress. 2013, Pubmed
Schneppenheim, von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. 2003, Pubmed
Schneppenheim, A common origin of the 4143insA ADAMTS13 mutation. 2006, Pubmed
Shang, Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts. 2006, Pubmed
Shibagaki, Novel compound heterozygote mutations (H234Q/R1206X) of the ADAMTS13 gene in an adult patient with Upshaw-Schulman syndrome showing predominant episodes of repeated acute renal failure. 2006, Pubmed
Shindo, ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function. 2000, Pubmed
Silverstein, Thrombotic thrombocytopenic purpura. The initial neurologic manifestations. 1968, Pubmed
Snider, Dissociation between the level of von Willebrand factor-cleaving protease activity and disease in a patient with congenital thrombotic thrombocytopenic purpura. 2004, Pubmed
Soejima, A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? 2001, Pubmed
Soejima, Analysis on the molecular species and concentration of circulating ADAMTS13 in Blood. 2006, Pubmed
Soejima, ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. 2003, Pubmed
Spiel, von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. 2008, Pubmed
Studt, Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. 2005, Pubmed
Stöcker, The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. 1995, Pubmed
Suzuki, Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets. 2004, Pubmed
Tao, Novel ADAMTS-13 mutations in an adult with delayed onset thrombotic thrombocytopenic purpura. 2006, Pubmed
Tao, Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS13 under flow conditions. 2005, Pubmed
Tati, Phenotypic expression of ADAMTS13 in glomerular endothelial cells. 2011, Pubmed
Terrell, The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. 2005, Pubmed
Tortorella, Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. 1999, Pubmed
Tsai, Inhibitors of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura. 2001, Pubmed
Tsai, Multimeric composition of endothelial cell-derived von Willebrand factor. 1989, Pubmed
Tsai, Pathophysiology of thrombotic thrombocytopenic purpura. 2010, Pubmed
Tsai, Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. 1994, Pubmed
Tsai, von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. 2001, Pubmed
Tsai, Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. 1996, Pubmed
Tsai, Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. 2002, Pubmed
Tsai, Shear stress and von Willebrand factor in health and disease. 2003, Pubmed
Tsai, Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. 1998, Pubmed
Turner, Human endothelial cells synthesize and release ADAMTS-13. 2006, Pubmed
Uchida, Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura. 2004, Pubmed
Uemura, Localization of ADAMTS13 to the stellate cells of human liver. 2005, Pubmed
Veyradier, Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. 2001, Pubmed
Veyradier, Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). 2004, Pubmed
Wada, Plasma cytokine levels in thrombotic thrombocytopenic purpura. 1992, Pubmed
Wagner, Biosynthesis of von Willebrand protein by human endothelial cells. Identification of a large precursor polypeptide chain. 1983, Pubmed
Waters, Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response. 2009, Pubmed
Wieberdink, High von Willebrand factor levels increase the risk of stroke: the Rotterdam study. 2010, Pubmed
Wohner, Modulation of the von Willebrand factor-dependent platelet adhesion through alternative proteolytic pathways. 2012, Pubmed
Xiang, Mechanism of von Willebrand factor scissile bond cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). 2011, Pubmed
Yiallouros, The roles of Glu93 and Tyr149 in astacin-like zinc peptidases. 2000, Pubmed
Yomtovian, Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature. 2004, Pubmed
Zheng, Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. 2001, Pubmed
Zheng, Cleavage of von Willebrand factor requires the spacer domain of the metalloprotease ADAMTS13. 2003, Pubmed
Zheng, Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. 2004, Pubmed
Zhou, ADAMTS13 is expressed in hepatic stellate cells. 2005, Pubmed
Zhou, Enzymatically active ADAMTS13 variants are not inhibited by anti-ADAMTS13 autoantibodies: a novel therapeutic strategy? 2005, Pubmed