Affinage

ADAMTS13

A disintegrin and metalloproteinase with thrombospondin motifs 13 · UniProt Q76LX8

Length
1427 aa
Mass
153.6 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAMTS13 is a plasma zinc metalloprotease that regulates hemostasis and vascular integrity by cleaving von Willebrand factor (VWF) at the Tyr1605-Met1606 bond within the A2 domain, thereby limiting the size and thrombogenic potential of ultra-large VWF multimers under fluid shear stress (PMID:11557746, PMID:12393399, PMID:21715306). The enzyme adopts a closed, autoinhibited conformation in which the distal T8-CUB2 domains fold back onto the proximal MDTCS catalytic module; binding of the VWF D4 domain to the distal domains relieves this autoinhibition and allosterically activates the metalloprotease active site, so that VWF serves as both the activating cofactor and the substrate (PMID:25512528, PMID:31439947, PMID:32196558). Efficient secretion of ADAMTS13 from hepatic and endothelial cells requires O-fucosylation of its thrombospondin type 1 repeats by POFUT2, and additional functionally active pools exist in platelets and glomerular endothelium (PMID:17395589, PMID:16176307, PMID:21720563). Hereditary deficiency or acquired inhibitory autoantibodies—predominantly IgG4 targeting the spacer domain (Arg660/Tyr661/Tyr665 epitope region)—cause accumulation of ultra-large VWF multimers and thrombotic thrombocytopenic purpura, while ADAMTS13 deficiency also exacerbates ischemic stroke, atherosclerosis, and thrombotic microangiopathy through VWF-dependent mechanisms (PMID:23233642, PMID:19965676, PMID:24261607, PMID:31409673).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Identification of the VWF-cleaving protease as a new ADAMTS family metalloprotease established its domain architecture—metalloprotease, disintegrin-like, TSR, Cys-rich, spacer, seven additional TSRs, and two CUB domains—providing the structural framework for all subsequent functional dissection.

    Evidence cDNA cloning, Northern blotting, and sequence analysis of the human gene

    PMID:11557746

    Open questions at the time
    • No three-dimensional structure yet available
    • Expression sites and regulation unknown
    • Catalytic mechanism not characterized
  2. 2002 High

    Recombinant ADAMTS13 reconstituted VWF multimer degradation identical to the plasma protease and was inhibited by acquired TTP patient plasma, formally proving that ADAMTS13 is the physiological VWF-cleaving protease and that autoantibodies cause its functional deficiency.

    Evidence Recombinant expression in HEK 293 cells with VWF multimer degradation assay and patient-plasma inhibition

    PMID:12393399

    Open questions at the time
    • Cleavage site specificity and kinetics not defined
    • Propeptide role unknown
    • In vivo relevance not yet demonstrated in genetic models
  3. 2003 High

    Demonstrating that the propeptide is dispensable for folding, secretion, and enzymatic activity—and that pro-ADAMTS13 can cleave pro-VWF intracellularly—established that ADAMTS13 is constitutively active, unlike most ADAMTS family members that require propeptide removal for activation.

    Evidence Propeptide deletion and furin-site mutagenesis in HeLa and furin-deficient LoVo cells with VWF cleavage assays

    PMID:12975358

    Open questions at the time
    • Whether intracellular cleavage is physiologically significant in vivo
    • Regulatory mechanisms controlling activity remain unknown
  4. 2005 High

    Discovery of functionally active ADAMTS13 in platelets and on the platelet surface (upregulated by thrombin) revealed a local, on-demand source of VWF-cleaving activity at sites of thrombus formation, beyond the known hepatic secretion.

    Evidence Platelet lysate VWF cleavage assay under static and flow conditions, flow cytometry, and inhibition by anti-ADAMTS13 antibody

    PMID:16176307

    Open questions at the time
    • Relative contribution of platelet versus plasma ADAMTS13 in vivo unknown
    • Mechanism of platelet ADAMTS13 storage and release not defined
  5. 2007 High

    Identification of O-fucosylation on six of eight TSR domains and its requirement for secretion established a critical post-translational quality-control step: POFUT2-dependent glycosylation is necessary for ADAMTS13 to exit the ER efficiently.

    Evidence Mass spectrometry, metabolic labeling, site-directed mutagenesis of O-fucose sites, and siRNA knockdown of POFUT2

    PMID:17395589

    Open questions at the time
    • Whether O-fucosylation also affects catalytic activity or stability in plasma
    • Role of the glucose-β1,3-fucose disaccharide versus fucose alone
  6. 2008 High

    Detailed enzymology of the Tyr1605-Met1606 cleavage reaction—revealing two catalytic ionizable groups, negative activation entropy, and a VWF A2 'hot spot' driving molecular recognition—provided the first kinetic and thermodynamic framework for ADAMTS13 catalysis.

    Evidence FRETS-VWF73 fluorescence quenching kinetics across pH and temperature; Co²⁺-substituted enzyme; product inhibition analysis

    PMID:18502798

    Open questions at the time
    • Structural basis of the two ionizable groups not resolved
    • Catalytic mechanism at atomic resolution still missing
  7. 2009 High

    Genetic knockout studies in stroke and gene-therapy models demonstrated that ADAMTS13 deficiency worsens ischemia-reperfusion injury via the VWF-platelet axis and that hematopoietic cell-derived ADAMTS13 can rescue plasma activity, establishing both the in vivo protective role and a potential therapeutic source.

    Evidence Middle cerebral artery occlusion in Adamts13⁻/⁻ mice; lentiviral transduction of hematopoietic progenitor cells with autologous transplantation and thrombosis assays

    PMID:19141866 PMID:19965676

    Open questions at the time
    • Contribution of brain endothelial ADAMTS13 versus circulating protease not separated
    • Optimal therapeutic delivery route undetermined
  8. 2010 High

    Mutagenesis of the metalloprotease domain identified two substrate-contacting variable regions (VR1: D187-R193 for efficiency; VR3: D252-P256 for P1' specificity), beginning to define the molecular determinants of ADAMTS13's exquisite VWF selectivity.

    Evidence Composite sequence swaps and point mutations with kinetic analysis using VWF115 substrate

    PMID:20647566

    Open questions at the time
    • Structure of the enzyme–substrate complex not yet solved
    • Full exosite map incomplete
  9. 2011 High

    Synthesis of biochemical and biophysical evidence established that shear-induced unfolding of the VWF A2 domain—not a classical protease inhibitor—is the primary regulatory mechanism controlling ADAMTS13 proteolysis, and that glomerular endothelial cells are a functionally relevant local source of the enzyme.

    Evidence Review integrating shear-dependent VWF unfolding and exosite mapping studies; real-time PCR, immunofluorescence, and VWF multimer analysis in human glomerular endothelial cells and Adamts13⁻/⁻ mice

    PMID:21715306 PMID:21720563

    Open questions at the time
    • Quantitative threshold of shear force needed for A2 domain unfolding in vivo not precisely defined
    • Relative importance of endothelial versus hepatic ADAMTS13 unclear
  10. 2012 Medium

    Mapping the autoantibody epitope in acquired TTP to the spacer domain surface (Arg660/Tyr661/Tyr665) explained how autoantibodies inhibit VWF binding and established the spacer domain as both a critical substrate-recognition exosite and the principal immunogenic target.

    Evidence Epitope mapping with patient autoantibodies, domain-specific inhibition studies, IgG subclass characterization

    PMID:23233642

    Open questions at the time
    • Whether epitope escape mutations can be engineered without loss of activity
    • T-cell epitopes driving the autoimmune response not mapped
  11. 2014 High

    Discovery of allosteric autoinhibition—where distal T8-CUB2 domains fold back on MDTCS and VWF D4 binding relieves this inhibition—fundamentally reframed ADAMTS13 as a conformationally regulated enzyme rather than a constitutively open protease, and genetic epistasis with VWF deficiency placed it upstream of VWF in atherosclerotic plaque progression.

    Evidence SAXS, domain truncation kinetics, and monoclonal antibody activation; Adamts13⁻/⁻/Vwf⁻/⁻/ApoE⁻/⁻ triple knockout mice on high-fat diet

    PMID:24261607 PMID:25512528

    Open questions at the time
    • Full-length structure in open and closed states not yet solved
    • Whether additional cofactors modulate the open-closed transition in vivo
  12. 2019 High

    The crystal structure of the MDTCS module revealed a latent active-site conformation requiring allosteric opening, and cross-species analysis showed that T7-T8 domains are specifically essential for VWF D4-mediated allosteric activation, while T3-T6 are dispensable.

    Evidence Crystal structure determination with kinetic exosite mutagenesis; domain deletion mutants tested across 20 vertebrate species for D4-induced activation and shear-dependent cleavage

    PMID:30700419 PMID:31439947

    Open questions at the time
    • Full-length structure in complex with VWF not available
    • Precise conformational pathway from closed to open state not resolved
  13. 2019 High

    Epistatic interaction between ADAMTS13 deficiency and complement factor H mutation synergistically producing thrombotic microangiopathy established that the ADAMTS13-VWF axis and complement pathway cooperate in TMA pathogenesis.

    Evidence Double-mutant Adamts13⁻/⁻ × cfh-R1206 mice with multiple hematologic and renal endpoints

    PMID:31409673

    Open questions at the time
    • Molecular mechanism linking VWF multimer accumulation to complement activation not defined
    • Whether complement inhibition can rescue ADAMTS13-deficient TMA
  14. 2020 High

    Kinetic dissection of conformational activation by anti-spacer and anti-CUB1 antibodies showed that allosteric relief of autoinhibition enhances kcat (not Km), clarifying that the autoinhibited conformation specifically restricts active-site catalytic turnover rather than substrate access, and refined epitope mapping identified three immunogenic hotspots in the spacer domain across 138 iTTP patients.

    Evidence kcat/Km determination with VWF A2 fragment proteolysis and conformational ELISA; library of 11 spacer-domain hybrids tested against 138 patient plasmas

    PMID:32196558 PMID:33171004

    Open questions at the time
    • Structural basis of kcat enhancement at atomic resolution unknown
    • Whether gain-of-function ADAMTS13 variants could evade autoantibodies therapeutically

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full-length structure of ADAMTS13 in complex with unfolded VWF, the precise conformational pathway from autoinhibited to active states, the physiological significance of the putative disulfide reductase activity of the distal domains, and the mechanistic basis by which ADAMTS13's C-terminal TSP1 repeats modulate angiogenesis independently of VWF proteolysis.
  • No full-length ADAMTS13–VWF complex structure
  • Disulfide reductase activity of CUB domains not validated independently
  • Angiogenic activity via TSP1 domains observed by a single group

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 4
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 1
Pathway
R-HSA-109582 Hemostasis 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2
Partners
CFHFURINPOFUT2VEGFAVWF

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ADAMTS13 (VWF-cleaving protease) was identified as a new member of the ADAMTS family of metalloproteases with a domain architecture including: signal peptide, short propeptide (with furin consensus RQRR), reprolysin-like metalloprotease domain, disintegrin-like domain, thrombospondin-1 repeat, Cys-rich domain, ADAMTS spacer, seven additional thrombospondin-1 repeats, and two CUB domains. The Cys-rich domain contains an RGDS sequence. Sites for Zn2+ and Ca2+ are conserved in the protease domain. cDNA cloning, Northern blotting, sequence analysis The Journal of biological chemistry High 11557746
2002 Recombinant ADAMTS13 expressed in HEK 293 cells degrades VWF multimers and proteolytically cleaves VWF to the same fragments as plasma VWF-cleaving protease, confirming that ADAMTS13 is responsible for physiological proteolytic degradation of VWF multimers. Recombinant ADAMTS13-mediated degradation was entirely inhibited by plasma from a patient with acquired TTP. Expression of recombinant ADAMTS13 in HEK 293 cells, VWF multimer degradation assay, inhibition by patient plasma Blood High 12393399
2003 The ADAMTS13 propeptide is not required for folding, secretion, or enzymatic activity. Furin is the protease responsible for propeptide cleavage. Secreted pro-ADAMTS13 (with intact propeptide) has normal proteolytic activity toward VWF. In cells co-expressing ADAMTS13 and VWF, pro-ADAMTS13 can cleave pro-VWF intracellularly. Propeptide deletion and furin consensus site mutagenesis, expression in HeLa and furin-deficient LoVo cells, VWF cleavage assay The Journal of biological chemistry High 12975358
2007 ADAMTS13 is O-fucosylated on at least six of its eight thrombospondin type 1 repeats (TSRs) with a glucose-β1,3-fucose disaccharide. This modification is required for efficient secretion of ADAMTS13; mutation of O-fucosylation sites or knockdown of POFUT2 (the transferase responsible) markedly reduces ADAMTS13 secretion. Mass spectral analysis of tryptic peptides, metabolic labeling with [3H]fucose, site-directed mutagenesis of modified serines, siRNA knockdown of POFUT2, GDP-fucose-deficient cell line The Journal of biological chemistry High 17395589
2010 The ADAMTS13 metalloprotease domain contains two subsites critical for VWF cleavage: residues D187-R193 (VR1) are important for cleavage efficiency (kcat/Km reduced 2–10 fold by point mutations D187A, R190A, R193A), and residues D252-P256 (VR3) influence P1' amino acid specificity, shaping the S1' substrate-binding pocket. Composite sequence swaps and single-point mutagenesis in variable regions; kinetic analysis using VWF115 substrate and P1'-mutated VWF substrates Blood High 20647566
2011 ADAMTS13 proteolysis of VWF is controlled not by inhibitors but by conformational changes in VWF induced by elevated rheological shear forces, which unfold the VWF A2 domain to reveal cryptic exosites and the scissile bond (Tyr1605-Met1606). ADAMTS13 makes multiple exosite interactions with the unfolded A2 domain to position itself for cleavage. Review synthesizing biochemical and biophysical studies; supported by experimental literature on shear-dependent VWF unfolding and ADAMTS13 exosite mapping Blood High 21715306
2008 ADAMTS13 catalysis of VWF A2-domain peptide (FRETS-VWF73) cleavage at Tyr1605-Met1606 is governed by two ionizable groups (pKa ~6.4 and ~4.0). The transition state is more ordered than the ground state (negative activation entropy). Residues Asp1653, Glu1655, Glu1660, Asp1663, and Thr1656 in the VWF A2 sequence form a 'hot spot' driving molecular recognition and allosteric regulation of ADAMTS13 binding. The product peptide (Met1606-Arg1668) acts as a hyperbolic mixed-type inhibitor. Fluorescence quenching (FRETS) kinetic assay across temperature and pH ranges; Co2+-substituted enzyme; product inhibition analysis; molecular modeling Biophysical journal High 18502798
2014 ADAMTS13 is allosterically regulated: the distal T8-CUB2 domains interact with and inhibit the proximal MDTCS catalytic domains. Binding of VWF D4 domain (or monoclonal antibodies) to the distal domains relieves this autoinhibition and markedly enhances substrate cleavage. Small angle X-ray scattering data support interdomain contact between distal T-CUB and proximal MDTCS domains in the closed, autoinhibited conformation. VWF D4-CUB binding assay, monoclonal antibody activation, kinetic proteolysis assays with truncation variants, small angle X-ray scattering (SAXS) Proceedings of the National Academy of Sciences of the United States of America High 25512528
2019 Crystal structure of ADAMTS13 (metalloprotease to spacer domains) reveals a latent conformation in which the active-site cleft is occluded, requiring allosteric change for substrate accommodation. Kinetic analyses show that cysteine-rich and spacer domain exosites bring enzyme and substrate into proximity, then disintegrin-like domain exosite binding to VWF allosterically activates the adjacent metalloprotease domain. VWF functions as both the activating cofactor and substrate. Crystal structure determination, kinetic analyses of VWF proteolysis by exosite mutants Nature communications High 31439947
2019 ADAMTS13 allosteric activation is conserved across vertebrates. The T7 and T8 distal thrombospondin domains are essential for allosteric activation by VWF D4 domain; deletion of T7 or T8 abolishes allosteric activation. Domains T3-T6 are dispensable for allosteric regulation and shear-dependent cleavage. Assay of ADAMTS13 from 20 placental mammals, birds, and amphibians; phylogenetic analysis; domain deletion mutants tested for VWF D4-induced activation and shear-dependent cleavage Blood High 30700419
2020 Conformational activation of ADAMTS13 by anti-Spacer (3E4) or anti-CUB1 (17G2) monoclonal antibodies enhances ADAMTS13 catalytic efficiency (kcat/Km) ~2-fold. The mechanism is allosteric enhancement of metalloprotease domain active site function (increased kcat), not exposure of Spacer or cysteine-rich exosites or improved substrate binding (Km unchanged). A cryptic metalloprotease domain epitope is exposed upon mAb-induced conformational extension. Kinetic analyses of VWF A2 domain fragment proteolysis; ELISA-based conformational assay; kcat and Km determination Blood advances High 32196558
2005 Platelets contain functionally active ADAMTS13. Platelet lysates cleave endothelial cell-derived ultra-large VWF under static and flow conditions in a divalent cation-dependent manner; cleavage is inhibited by EDTA and by anti-ADAMTS13 antibody from a TTP patient. ADAMTS13 surface expression on platelets increases upon activation by thrombin receptor-activating peptide but not ADP. VWF cleavage assays with platelet lysates, antibody inhibition, flow cytometry, immunoblotting with four domain-specific antibodies Journal of thrombosis and haemostasis : JTH High 16176307
2011 Glomerular endothelial cells express and secrete functionally active ADAMTS13, which cleaves VWF. ADAMTS13 deficiency in mice results in thickening of glomerular capillaries with platelet deposition on the vessel wall. Real-time PCR, flow cytometry, immunofluorescence, immunoblotting, VWF multimer analysis in human glomerular endothelial cells; immunohistochemistry and electron microscopy in wild-type vs. Adamts13−/− mice PloS one High 21720563
2009 ADAMTS13 deficiency aggravates ischemic brain damage in mice via the VWF-platelet axis: after reperfusion, Adamts13−/− mice show markedly decreased regional cerebral blood flow and larger infarct volumes compared to wild-type mice, demonstrating that ADAMTS13 protects against ischemia-reperfusion injury by regulating VWF-platelet interactions. Middle cerebral artery occlusion model in Adamts13−/− vs. wild-type mice; cerebral blood flow measurement; infarct volume quantification Blood High 19965676
2013 The N-terminal MDTCS portion of ADAMTS13 is necessary and sufficient for proteolytic cleavage of VWF and attenuation of arterial/venous thrombosis. The distal portion (TSP1 2-8 repeats and CUB domains) may function as a disulfide bond reductase to prevent elongation of ultra-large VWF strings on activated endothelial cells. Proteolytic cleavage of VWF by ADAMTS13 is accelerated by FVIII and platelets under fluid shear stress; disruption of FVIII (or platelet glycoprotein 1bα)–VWF interactions dramatically impairs ADAMTS13-dependent proteolysis in vitro and in vivo. Domain truncation variants, thrombosis models in Adamts13−/− mice, in vitro VWF cleavage assays under flow Journal of thrombosis and haemostasis : JTH High 23809107
2014 ADAMTS13 modulates atherosclerotic plaque progression through a VWF-dependent mechanism: deficiency of VWF in Adamts13−/−/ApoE−/− triple knockout mice completely reverses exacerbated atherosclerosis, macrophage/neutrophil infiltration, and interstitial collagen content compared with Adamts13−/−/ApoE−/− mice. Genetic epistasis using Adamts13−/−/Vwf−/−/ApoE−/− triple knockout mice on high-fat diet; aortic sinus cross-section analysis; immunohistochemistry Journal of thrombosis and haemostasis : JTH High 24261607
2012 Recombinant full-length ADAMTS13 promotes endothelial tube formation, proliferation, and migration in a dose-dependent manner independent of VEGF. ADAMTS13 also inhibits VEGF-induced angiogenesis, and these effects are mediated through the C-terminal TSP1 domains. Co-immunoprecipitation shows ADAMTS13 binds to VEGF via its TSP1 domain. Matrigel tube formation assay, proliferation counting assay, Boyden chamber migration assay, antibody blockade, truncation variants, co-immunoprecipitation Microvascular research Medium 22626948
2014 ADAMTS13 promotes angiogenesis via upregulation of VEGF expression and VEGFR2 phosphorylation in endothelial cells. The C-terminal TSP1 repeats (domains 2-8) are responsible for this angiogenic activity, as shown by structure-function analysis with truncation variants. Anti-VEGF IgG abrogates TSP1-domain-mediated effects on proliferation, migration, and VEGFR2 phosphorylation. Western blot, ELISA, VEGFR2 phosphorylation assay, proliferation and chemotaxis assays with TSP1-domain truncation variants and anti-VEGF antibody Cellular and molecular life sciences : CMLS Medium 24950743
2009 Autologous transplantation of hematopoietic progenitor cells transduced with lentiviral vector encoding ADAMTS13 restores plasma ADAMTS13 activity in Adamts13−/− mice, reduces VWF multimer size, and significantly prolongs ferric chloride-induced carotid arterial occlusion time, establishing hematopoietic cells as a source of functional ADAMTS13. Lentiviral transduction of hematopoietic progenitor cells, autologous transplantation in Adamts13−/− mice, plasma ADAMTS13 activity assay, VWF multimer analysis, ferric chloride thrombosis model Blood High 19141866
2017 ADAMTS13 controls vascular remodeling after ischemic stroke by modifying VWF reactivity. ADAMTS13-deficient mice show reduced neovascularization, impaired capillary perfusion, pericyte loss, and accelerated blood-brain barrier breakdown after stroke. VWF deficiency or anti-VWF antibody treatment reversed these deficits in Adamts13−/− mice, placing ADAMTS13 upstream of VWF in post-stroke angiogenesis. Adamts13−/−, Vwf−/−, and double-knockout mice in stroke model; microvascular analysis; angiopoietin-2 and galectin-3 measurement; adenoviral and recombinant protein rescue experiments; VEGFR2 antagonist Blood High 28428179
2019 ADAMTS13 deficiency combined with complement factor H (cfh) heterozygous mutation (cfh R1206) synergistically induces thrombotic microangiopathy in mice, whereas either single defect alone does not cause overt disease, demonstrating epistatic interaction between the ADAMTS13-VWF axis and complement activation in TMA pathogenesis. Genetic epistasis using Adamts13−/−, cfh-mutant, and double-mutant mice; platelet counts, haptoglobin, erythrocyte fragmentation, LDH, BUN, creatinine, histology, immunohistochemistry Blood High 31409673
2005 The transcriptional activity of the ADAMTS13 gene is not significantly altered by proinflammatory stimuli (endotoxin, TNF-α, IL-6, IL-1β), immunosuppressive agents (cyclosporine A, steroids, doxycycline), suggesting that diminished ADAMTS13 activity observed under various clinical conditions is not primarily due to transcriptional regulation. RNA analysis in liver homogenates and Hep3B liver cell culture; stimulation with multiple agents; in silico promoter analysis Thrombosis and haemostasis Medium 16113782
2015 Platelet-delivered recombinant ADAMTS13 (expressed in transgenic platelets) is released upon stimulation with thrombin and collagen, inhibits arterial thrombosis after vascular injury, and prevents TTP syndrome in mice even in the absence of plasma ADAMTS13 activity or in the presence of anti-ADAMTS13 autoantibodies. Transgenic mice expressing ADAMTS13 in platelets, Western blot, FRET activity assay, ferric chloride thrombosis model, Shigatoxin-2 and VWF-induced TTP models Blood High 25800050
2012 The epitope targeted by inhibitory anti-ADAMTS13 autoantibodies in acquired TTP is primarily within the spacer domain, specifically a surface comprising Arg660, Tyr661, and Tyr665, which contributes to productive binding of ADAMTS13 to unfolded VWF. IgG autoantibodies are predominantly of the IgG4 subclass. Epitope mapping, patient autoantibody characterization, domain-specific inhibition studies Hematology. American Society of Hematology. Education Program Medium 23233642
2020 The immunogenic hotspots in the ADAMTS13 spacer domain targeted by anti-spacer autoantibodies in iTTP are amino acid regions 588-592, 602-610, and 657-666, identified using a library of 11 full-length ADAMTS13 spacer hybrids with corresponding ADAMTS1 spacer regions substituted. Library of 11 spacer hybrid ADAMTS13 proteins; ELISA epitope mapping with 138 iTTP patient plasma samples Journal of thrombosis and haemostasis : JTH High 33171004

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. The Journal of biological chemistry 667 11557746
2005 Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. Molecular cell 388 16364915
2019 RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy 382 31679460
2013 Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochimica et biophysica acta 331 23428348
2012 STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nature reviews. Nephrology 290 22986360
2011 Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 234 21715306
2002 Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 190 12393399
2002 von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 157 12393505
2011 Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. Journal of thrombosis and haemostasis : JTH 151 21781265
2011 The roles of TTP and BRF proteins in regulated mRNA decay. Wiley interdisciplinary reviews. RNA 132 21278925
2015 Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay. eLife 110 25815583
2006 ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. Blood 109 17053057
2009 ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion. Blood 104 19965676
2013 Structure-function and regulation of ADAMTS-13 protease. Journal of thrombosis and haemostasis : JTH 103 23809107
2014 Allosteric activation of ADAMTS13 by von Willebrand factor. Proceedings of the National Academy of Sciences of the United States of America 101 25512528
2003 Cleavage of the ADAMTS13 propeptide is not required for protease activity. The Journal of biological chemistry 95 12975358
2017 ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery. Blood 94 28428179
2007 O-fucosylation is required for ADAMTS13 secretion. The Journal of biological chemistry 87 17395589
2005 Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. Journal of thrombosis and haemostasis : JTH 86 16176307
2020 Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13. Frontiers in immunology 85 33343584
2021 Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis. Seminars in thrombosis and hemostasis 80 33893632
2017 Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan. International journal of hematology 74 28550351
2019 Crystal structure and substrate-induced activation of ADAMTS13. Nature communications 70 31439947
2004 von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Seminars in hematology 70 14727254
2002 ADAMTS13 and TTP. Current opinion in hematology 65 12172456
2009 Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008). Kidney international. Supplement 63 19180126
2021 ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. Journal of thrombosis and haemostasis : JTH 60 34053187
2012 Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Hematology. American Society of Hematology. Education Program 57 23233642
2023 Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis. Metabolism: clinical and experimental 55 36773805
2017 Aryl hydrocarbon receptor inhibits inflammation in DSS‑induced colitis via the MK2/p‑MK2/TTP pathway. International journal of molecular medicine 53 29207040
2017 The RNA-binding protein Tristetraprolin (TTP) is a critical negative regulator of the NLRP3 inflammasome. The Journal of biological chemistry 52 28302726
2016 Von Willebrand Factor, ADAMTS13, and the Risk of Mortality: The Rotterdam Study. Arteriosclerosis, thrombosis, and vascular biology 52 27737864
2008 Correction of ADAMTS13 deficiency by in utero gene transfer of lentiviral vector encoding ADAMTS13 genes. Molecular therapy : the journal of the American Society of Gene Therapy 50 18957966
2013 Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. Hematology (Amsterdam, Netherlands) 48 23433535
2018 TTP-like syndrome: novel concept and molecular pathogenesis of endotheliopathy-associated vascular microthrombotic disease. Thrombosis journal 47 30127669
2019 GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling. Cell reports 46 30917308
2016 Dysregulation of TTP and HuR plays an important role in cancers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 46 27644249
2016 Activating protein phosphatase 2A (PP2A) enhances tristetraprolin (TTP) anti-inflammatory function in A549 lung epithelial cells. Cellular signalling 43 26820662
2012 ADAMTS13 promotes angiogenesis and modulates VEGF-induced angiogenesis. Microvascular research 42 22626948
2015 Tristetraprolin (TTP) coordinately regulates primary and secondary cellular responses to proinflammatory stimuli. Journal of leukocyte biology 41 25657290
2012 Thrombotic microangiopathies, thrombotic thrombocytopenic purpura, and ADAMTS-13. Seminars in thrombosis and hemostasis 41 22314603
2017 Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP). Journal for immunotherapy of cancer 40 28344807
2021 α-Tocopherol transfer protein (α-TTP). Free radical biology & medicine 39 34563650
2022 Mechanisms of ADAMTS13 regulation. Journal of thrombosis and haemostasis : JTH 38 36074019
2019 The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension. The European respiratory journal 38 30655285
2019 Synergistic effects of ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy. Blood 38 31409673
2002 Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Journal of molecular medicine (Berlin, Germany) 38 12395148
2017 Plasma exchange in thrombotic microangiopathies (TMAs) other than thrombotic thrombocytopenic purpura (TTP). Hematology. American Society of Hematology. Education Program 37 29222314
2013 Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry. Hamostaseologie 37 23715103
2008 Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatric nephrology (Berlin, Germany) 37 18574602
2020 Antibodies that conformationally activate ADAMTS13 allosterically enhance metalloprotease domain function. Blood advances 36 32196558
2021 Laboratory testing for ADAMTS13: Utility for TTP diagnosis/exclusion and beyond. American journal of hematology 35 33991361
2010 The ADAMTS13 metalloprotease domain: roles of subsites in enzyme activity and specificity. Blood 35 20647566
2020 Cross-talk between CD38 and TTP Is Essential for Resolution of Inflammation during Microbial Sepsis. Cell reports 34 31995750
2014 ADAMTS13 modulates atherosclerotic plaque progression in mice via a VWF-dependent mechanism. Journal of thrombosis and haemostasis : JTH 34 24261607
2014 Acquired TTP: ADAMTS13 meets the immune system. Blood reviews 34 25213289
2019 The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3. Journal of immunology (Baltimore, Md. : 1950) 33 31527197
2014 The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs. Blood 33 25261198
2018 ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function. American journal of physiology. Renal physiology 32 30461292
2015 Platelet-delivered ADAMTS13 inhibits arterial thrombosis and prevents thrombotic thrombocytopenic purpura in murine models. Blood 32 25800050
2014 Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. Seminars in thrombosis and hemostasis 32 24802084
2011 Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura. Journal of thrombosis and haemostasis : JTH 32 21535387
2009 Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell-mediated gene therapy. Blood 32 19141866
2009 Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS) / thrombocytic thrombopenic purpura (TTP). Thrombosis and haemostasis 31 19190808
2023 Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) in Japan 2023. International journal of hematology 30 37689812
2022 Advances in the management of TTP. Blood reviews 30 35216839
2017 Thrombotic Microangiopathies (TTP, HUS, HELLP). Hematology/oncology clinics of North America 30 29078925
2014 Effect of recombinant ADAMTS-13 on microthrombosis and brain injury after experimental subarachnoid hemorrhage. Journal of thrombosis and haemostasis : JTH 29 24679129
2014 ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2. Cellular and molecular life sciences : CMLS 29 24950743
2021 TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation. JCI insight 28 34877932
2018 ADAMTS13: origins, applications, and prospects. Transfusion 28 30208220
2017 Cu(I) Disrupts the Structure and Function of the Nonclassical Zinc Finger Protein Tristetraprolin (TTP). Inorganic chemistry 28 28557421
2005 Pathogenesis of thrombotic thrombocytopenic purpura: ADAMTS13 deficiency and beyond. Seminars in thrombosis and hemostasis 28 16388413
2019 Phylogenetic and functional analysis of ADAMTS13 identifies highly conserved domains essential for allosteric regulation. Blood 27 30700419
2013 p38 MAPK/PP2Acα/TTP pathway on the connection of TNF-α and caspases activation on hydroquinone-induced apoptosis. Carcinogenesis 27 23288922
2021 Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis. Blood advances 26 34505883
2012 EGF activates TTP expression by activation of ELK-1 and EGR-1 transcription factors. BMC molecular biology 26 22433566
2020 A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells. Genome biology 25 32039742
2015 Increased expressions of ADAMTS-13 and apoptosis contribute to neuropathology during Toxoplasma gondii encephalitis in mice. Neuropathology : official journal of the Japanese Society of Neuropathology 25 26542631
2016 Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies. Immunobiology 24 27771173
2013 HUS and TTP in Children. Pediatric clinics of North America 24 24237985
2005 Interplay between ADAMTS13 and von Willebrand factor in inherited and acquired thrombotic microangiopathies. Seminars in hematology 23 15662617
2019 The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma. Cancers 22 31717307
2022 The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer. Healthcare (Basel, Switzerland) 21 35327035
2011 Phenotypic expression of ADAMTS13 in glomerular endothelial cells. PloS one 21 21720563
2008 Mechanistic studies on ADAMTS13 catalysis. Biophysical journal 21 18502798
2020 Immunogenic hotspots in the spacer domain of ADAMTS13 in immune-mediated thrombotic thrombocytopenic purpura. Journal of thrombosis and haemostasis : JTH 20 33171004
2020 COVID-19 presenting as thrombotic thrombocytopenic purpura (TTP). BMJ case reports 20 33334760
2019 Doxorubicin inhibits PD-L1 expression by enhancing TTP-mediated decay of PD-L1 mRNA in cancer cells. Biochemical and biophysical research communications 20 31767150
2005 Transcriptional regulation of ADAMTS13. Thrombosis and haemostasis 20 16113782
2018 mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice. Scientific reports 19 29777164
2022 Evidence of protective effects of recombinant ADAMTS13 in a humanized model of sickle cell disease. Haematologica 18 35443560
2018 A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency. Molecular and cellular biology 18 29203639
2008 Tristetraprolin (TTP) gene polymorphisms in patients with rheumatoid arthritis and healthy individuals. Modern rheumatology 18 18536977
2013 Proteolytic processing of von Willebrand factor by adamts13 and leukocyte proteases. Mediterranean journal of hematology and infectious diseases 17 24106608
2022 Clinical implications of tristetraprolin (TTP) modulation in the treatment of inflammatory diseases. Pharmacology & therapeutics 16 35525391
2018 The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin. PLoS genetics 16 29723192
2001 Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS): the new thinking. Journal of thrombosis and thrombolysis 15 11577265
2024 ADAMTS13 in the New Era of TTP. International journal of molecular sciences 14 39125707
2017 A balancing act: RNA binding protein HuR/TTP axis in endometriosis patients. Scientific reports 14 28724967