Pathological Allostery in ADAMTS13: Autoantibody-Induced Modulation and Its Role in Immune Thrombotic Thrombocytopenic Purpura (iTTP).

Background/

Objectives

ADAMTS13 is a plasma metalloprotease that cleaves von Willebrand Factor (vWF), a multimeric glycoprotein involved in platelet recruitment during primary hemostasis. Inhibition of ADAMTS13 activity by autoantibodies causes immune thrombotic thrombocytopenic purpura (iTTP). Growing evidence has established allostery as a key contributor to iTTP pathophysiology. This review summarizes the current understanding of how ADAMTS13 structure contributes to its function and regulation and examines anti-ADAMTS13 antibodies as pathological allosteric modulators in iTTP and their associated allosteric mechanisms.

Methods

We searched the published literature investigating the role of allostery in iTTP, with special emphasis on studies that satisfy the functional definition of allostery, which addresses how a ligand binding to a protein influences a second ligand-binding event at a distinct site.

Results

Anti-ADAMTS13 antibodies primarily affect catalytic turnover as opposed to substrate binding affinity, consistent with their characterization as V-type allosteric ligands. Biophysical studies have revealed extensive and distal structural changes upon antibody binding, including near the enzyme's active site. However, more recent work utilizing full-length Immunoglobulin G (IgG) molecules and polyclonal iTTP patient plasma suggests that the mechanistic complexity is greater than initially appreciated, with multiple mechanisms likely coexisting.

Conclusions

While significant progress has been made to understand allostery in ADAMTS13 and iTTP, many questions remain unresolved. Further elucidation of these underlying mechanisms could help inform the development of diagnostic strategies and targeted therapies for this potentially fatal disorder.