Proposed mechanism of ADAMTS13 inhibition by antispacer domain autoantibodies. ADAMTS13 with metalloprotease (M), disintegrin (D), 8 thrombospondin-type 1 (T1-8), cysteine-rich (C), spacer (S), and 2 CUB (CUB1,2) domains and VWF subunit with stretched A2 domain. ADAMTS13 inhibiting antispacer domain antibodies (1) bind to the spacer domain epitope (exosite 3), not merely inhibit exosite 3 interaction with VWF A2 domain (2), but exert an allosteric effect on the metalloprotease domain (3), impairing its access to the Y1605-M1606 cleavage site in the VWF A2 domain (4). Professional illustration by Patrick Lane, ScEYEnce Studios.

Proposed mechanism of ADAMTS13 inhibition by antispacer domain autoantibodies. ADAMTS13 with metalloprotease (M), disintegrin (D), 8 thrombospondin-type 1 (T1-8), cysteine-rich (C), spacer (S), and 2 CUB (CUB1,2) domains and VWF subunit with stretched A2 domain. ADAMTS13 inhibiting antispacer domain antibodies (1) bind to the spacer domain epitope (exosite 3), not merely inhibit exosite 3 interaction with VWF A2 domain (2), but exert an allosteric effect on the metalloprotease domain (3), impairing its access to the Y1605-M1606 cleavage site in the VWF A2 domain (4). Professional illustration by Patrick Lane, ScEYEnce Studios.

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