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].

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