ADAMTS13 conformations and mechanism of inhibition in immune thrombotic thrombocytopenic purpura

Abstract

ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor, is crucial for normal hemostasis. Acquired autoantibody-mediated deficiency of plasma ADAMTS13 results in a potentially fatal blood disorder, immune thrombotic thrombocytopenic purpura (iTTP). Plasma ADAMTS13 protease appears to exist in multiple conformations. Under physiological conditions, plasma ADAMTS13 exists predominantly in its "closed" conformation (or latent form), which may be activated by lowering pH, ligand binding, and binding of an antibody against the distal domains of ADAMTS13. In patients with iTTP, polyclonal antibodies target at various domains of ADAMTS13. However, nearly all inhibitory antibodies bind the spacer domain, whereas antibodies that bind the distal C-terminal domains may activate ADAMTS13 through removing its allosteric inhibition. Additionally, the anti-C-terminal antibodies may alter the potency of inhibitory antibodies towards ADAMTS13 activity. This review summarizes some of the most recent knowledge about the ADAMTS13 conformation and its mechanism of inhibition by its autoantibodies.

Keywords: ADAMTS13; TTP/HUS; activation; autoantibody; inhibition.

FIGURE 1

The primary domain structure of ADAMTS13 and proposed binding interaction between CUB and spacer domain. (A) ADAMTS13 consists of a metalloprotease, a disintegrin, the first TSP1 repeat, Cys-rich and spacer domain, followed by seven more TSP1 repeats, and two CUB domains. (B) Multiple binding regions in the Spacer interface including exosite 3 (R568, F592, R660, Y661, Y665), G607-S610, and exosite 4 (E634, D635, and R636) appear to interact with the CUB1 domain (E1231, R1251, L1258, D1259, and T1261) to mediate autoinhibition (Adapted from Yang et al.).

FIGURE 2

Conformational changes of ADAMTS13 induced by antibodies. (A) Transition from closed to open conformation of ADAMTS13 upon its binding with a human monoclonal anti-CUB IgG (scFv3–3) and its subsequent cleavage of VWF73 peptide. (B) The possible mechanism underlying the synergistic effect of a stimulating anti-CUB (scFv3–3) and an inhibitory anti-Spacer (i.e., scFv4–20) on proteolytic cleavage of VWF substrate (i.e., VWF73) by ADAMTS13 (Adapted from Halkidis and Zheng)