Schematic representation of 2 conformations of ADAMTS13, ADAMTS13-autoantibody complex, and NGLY3-ADAMTS13 variant. (A) Closed conformation of ADAMTS13. The closed conformation is maintained via an interaction of the S domain with the C-terminal CUB domains that diminishes its proteolytic activity. (B) Open conformation of ADAMTS13. The exosites in the D, C, and S domains bind to the unfolded A2 polypeptide chain (orange), and the binding enhances the proteolytic function of the M domain. (C) Binding of anti-ADAMTS13 S domain autoantibodies to the S domain. The binding interferes with the proteolytic function. (D) NGLY3-ADAMTS13 variant. The variant has an N-glycan at position 608 (red line) that interferes with the binding of anti-ADAMTS13 S domain autoantibodies, but not the binding of the unfolded A2 polypeptide chain. The conformational state of the variant is uncertain.