ArticleProceedings of the National Academy of Sciences of the United States of America2015
High-resolution epitope mapping by HX MS reveals the pathogenic mechanism and a possible therapy for autoimmune TTP syndrome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 59 citations in OpenAlex.
- 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
- Rat models of thrombotic thrombocytopenic purpura reveal crucial role of placental ADAMTS13 in perinatal survival.Blood advances · 2026Article
- Hydrogen Exchange Mass Spectrometry (HX-MS) for Mapping Antibody Binding Sites and Conformational Dynamics of ADAMTS13.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Arginine Methylation by PRMT1 Affects ADAMTS13 Secretion and Enzymatic Activity.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura.Scientific reports · 2025Article
- Mechanistic insight into multiple antibody binding to ADAMTS13 in immune thrombotic thrombocytopenic purpura.Research and practice in thrombosis and haemostasis · 2024Article
- Probe capsid structure stability and dynamics of adeno-associated virus as an important viral vector for gene therapy by hydrogen-deuterium exchange-mass spectrometry.Protein science : a publication of the Protein Society · 2024Article
- Introductory comments about the special series of thrombotic microangiopathy.Annals of blood · 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
- Mechanisms of inhibition of human monoclonal antibodies in immune thrombotic thrombocytopenic purpura.Blood · 2023Article
- Optimizing the Safety and Efficacy of Bio-Radiopharmaceuticals for Cancer Therapy.Pharmaceutics · 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
- Hydrogen Deuterium Exchange and other Mass Spectrometry-based Approaches for Epitope Mapping.Frontiers in analytical science · 2023Article
- Mapping Epitopes by Phage Display.Methods in molecular biology (Clifton, N.J.) · 2023Article
- ADAMTS13 protease or lack of von Willebrand factor protects irradiation and melanoma-induced thrombotic microangiopathy in zebrafish.Journal of thrombosis and haemostasis : JTH · 2022Article
- ADAMTS13 conformations and mechanism of inhibition in immune thrombotic thrombocytopenic purpura.Journal of thrombosis and haemostasis : JTH · 2022Review
- Cardiac troponin T and autoimmunity in skeletal muscle aging.GeroScience · 2022Article
- TTP: From empiricism for an enigmatic disease to targeted molecular therapies.British journal of haematology · 2022Review
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
Acquired thrombotic thrombocytopenic purpura (TTP), a thrombotic disorder that is fatal in almost all cases if not treated promptly, is primarily caused by IgG-type autoantibodies that inhibit the ability of the ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) metalloprotease to cleave von Willebrand factor (VWF). Because the mechanism of autoantibody-mediated inhibition of ADAMTS13 activity is not known, the only effective therapy so far is repeated whole-body plasma exchange. We used hydrogen-deuterium exchange mass spectrometry (HX MS) to determine the ADAMTS13 binding epitope for three representative human monoclonal autoantibodies, isolated from TTP patients by phage display as tethered single-chain fragments of the variable regions (scFvs). All three scFvs bind the same conformationally discontinuous epitopic region on five small solvent-exposed loops in the spacer domain of ADAMTS13. The same epitopic region is also bound by most polyclonal IgG autoantibodies in 23 TTP patients that we tested. The ability of ADAMTS13 to proteolyze VWF is impaired by the binding of autoantibodies at the epitopic loops in the spacer domain, by the deletion of individual epitopic loops, and by some local mutations. Structural considerations and HX MS results rule out any disruptive structure change effect in the distant ADAMTS13 metalloprotease domain. Instead, it appears that the same ADAMTS13 loop segments that bind the autoantibodies are also responsible for correct binding to the VWF substrate. If so, the autoantibodies must prevent VWF proteolysis simply by physically blocking normal ADAMTS13 to VWF interaction. These results point to the mechanism for autoantibody action and an avenue for therapeutic intervention.
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