ArticleBlood advances2020
Antibodies that conformationally activate ADAMTS13 allosterically enhance metalloprotease domain function.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 39 citations in OpenAlex.
- Unbiased plasma proteomics reveals hemolysis during ADAMTS13 relapse in patients with immune TTP.Blood advances · 2026Article
- The absence of ADAMTS13 improves early outcomes in an experimental model of trauma with uncontrolled hemorrhage.The journal of trauma and acute care surgery · 2026Article
- Human monoclonal and polyclonal anti-ADAMTS13 antibodies in immune thrombotic thrombocytopenic purpura: variable mechanisms of inhibition.Journal of thrombosis and haemostasis : JTH · 2026Article
- Pathological Allostery in ADAMTS13: Autoantibody-Induced Modulation and Its Role in Immune Thrombotic Thrombocytopenic Purpura (iTTP).Pharmaceuticals (Basel, Switzerland) · 2026Review
- Novel cryptic ADAMTS13 epitopes uncover a distinct open ADAMTS13 conformation in immune-mediated TTP.Haematologica · 2026Article
- A novel role for ADAMTS13 in hyperfibrinolysis after trauma-induced shockBritish journal of anaesthesia · 2026Article
- The landscape of ADAMTS13-related tests in thrombotic thrombocytopenic purpura: a review.Frontiers in medicine · 2026Review
- Determining ADAMTS13 Conformation for the Diagnosis of Immune Thrombotic Thrombocytopenic Purpura and Prediction of Relapse.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Trp1250, Lys1252, and Arg1367 of ADAMTS13 comprise a hot spot for anti-CUB domain antibodies in patients with iTTP.Blood advances · 2025Article
- Open or closed? Understanding the molecular mechanisms and clinical implications of ADAMTS13's conformation.HemaSphere · 2025Review
- Unraveling antibody-induced structural dynamics in the ADAMTS13 CUB1-2 domains via HDX-MS.Blood advances · 2025Article
- Arginine Methylation by PRMT1 Affects ADAMTS13 Secretion and Enzymatic Activity.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Mechanistic insight into multiple antibody binding to ADAMTS13 in immune thrombotic thrombocytopenic purpura.Research and practice in thrombosis and haemostasis · 2024Article
- Mechanism underlying severe deficiency of plasma ADAMTS-13 activity in immune thrombotic thrombocytopenic purpura.Journal of thrombosis and haemostasis : JTH · 2024Article
- Immune thrombotic thrombocytopenic purpura: pathogenesis and novel therapies: a narrative review.Annals of blood · 2023Article
- A novel von Willebrand factor multimer ratio as marker of disease activity in thrombotic thrombocytopenic purpura.Blood advances · 2023Observational
- Mechanisms of inhibition of human monoclonal antibodies in immune thrombotic thrombocytopenic purpura.Blood · 2023Article
- Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity.Haematologica · 2023Article
- A novel mechanism underlying allosteric regulation of ADAMTS-13 revealed by hydrogen-deuterium exchange plus mass spectrometry.Research and practice in thrombosis and haemostasis · 2023Article
- ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation.Journal of thrombosis and haemostasis : JTH · 2022Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Plasma ADAMTS13 circulates in a folded conformation that is stabilized by an interaction between the central Spacer domain and the C-terminal CUB (complement components C1r and C1s, sea urchin protein Uegf, and bone morphogenetic protein-1) domains. Binding of ADAMTS13 to the VWF D4(-CK) domains or to certain activating murine monoclonal antibodies (mAbs) induces a structural change that extends ADAMTS13 into an open conformation that enhances its function. The objective was to characterize the mechanism by which conformational activation enhances ADAMTS13-mediated proteolysis of VWF. The activating effects of a novel anti-Spacer (3E4) and the anti-CUB1 (17G2) mAbs on the kinetics of proteolysis of VWF A2 domain fragments by ADAMTS13 were analyzed. mAb-induced conformational changes in ADAMTS13 were investigated by enzyme-linked immunosorbent assay. Both mAbs enhanced ADAMTS13 catalytic efficiency (kcat/Km) by ∼twofold (3E4: 2.0-fold; 17G2: 1.8-fold). Contrary to previous hypotheses, ADAMTS13 activation was not mediated through exposure of the Spacer or cysteine-rich domain exosites. Kinetic analyses revealed that mAb-induced conformational extension of ADAMTS13 enhances the proteolytic function of the metalloprotease domain (kcat), rather than augmenting substrate binding (Km). A conformational effect on the metalloprotease domain was further corroborated by the finding that incubation of ADAMTS13 with either mAb exposed a cryptic epitope in the metalloprotease domain that is normally concealed when ADAMTS13 is in a closed conformation. We show for the first time that the primary mechanism of mAb-induced conformational activation of ADAMTS13 is not a consequence of functional exosite exposure. Rather, our data are consistent with an allosteric activation mechanism on the metalloprotease domain that augments active site function.
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