Modeling of the spacer domain and VWF-A2 interaction. (A) Surface representation of proximal C-terminal DTCS fragment of ADAMTS13. (B) Close-up view of the hydrophobic cluster in the exosite 3 in the spacer domain of ADAMTS13. This pocket contains a cluster of hydrophobic residues (L591, F592, L637, P638, L668, T669, and ring of Y661 and Y665), lined by basic residues (R568, R589, R636, and R660), supported by 8 β-sheets (ie, β1, 2, 3, 6, 7, 8, 9, and 10). (C) A substitution of these surface residues with those in yellow appears to increase hydrophobicity of this pocket. (D) VWF-A2 (1653-1668) forms an amphipathic helix (α6). Hydrophobic residues facing to the top and charged residues to the bottom. This amphipathic helix may govern specificity to the exosite 3 in the spacer domain by inserting its hydrophobic side into the pocket.