Affinage

ADAMTS13

A disintegrin and metalloproteinase with thrombospondin motifs 13 · UniProt Q76LX8

Length
1427 aa
Mass
153.6 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAMTS13 is a plasma zinc metalloprotease that regulates hemostasis by cleaving the Tyr1605-Met1606 bond in the von Willebrand factor (VWF) A2 domain, the physiologic VWF-cleaving activity confirmed by reconstitution with recombinant enzyme (PMID:11557746, PMID:12393399). Cleavage is markedly enhanced when VWF is bound to platelets via GPIbalpha under fluid shear stress, preferentially consuming large, prothrombotic VWF multimers (PMID:17901248), and the enzyme is released constitutively from the Golgi of endothelial cells to cleave cell-anchored VWF strings (PMID:19822897). Catalysis is allosterically controlled by a closed-to-open conformational switch: distal T8-CUB domains autoinhibit the metalloprotease active site through interactions with the proximal MDTCS region, and binding of the VWF D4 domain (or activating antibodies) to T7/T8-CUB relieves this autoinhibition by increasing kcat and opening the occluded active-site cleft (PMID:25512528, PMID:31439947, PMID:30700419, PMID:32196558). Substrate engagement is staged through cysteine-rich and spacer exosites that dock VWF, followed by a disintegrin-like domain exosite that allosterically activates the protease, with metalloprotease subsites VR1/VR3 and CUB-domain N-glycans tuning specificity and the conformational equilibrium (PMID:20647566, PMID:31439947, PMID:28370891). Beyond VWF proteolysis, ADAMTS13 acts through its TSP1 repeats to promote angiogenesis by inducing VEGF expression and VEGFR2/AKT signaling (PMID:22626948, PMID:24950743, PMID:28546076), and protects vascular beds in a VWF-dependent manner across atherosclerosis, diabetic nephropathy, and stroke models (PMID:24261607, PMID:28495930, PMID:28428179). Mutations in ADAMTS13 that impair secretion, catalysis, or the spacer-CUB conformational interaction cause congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome), and patient autoantibodies against the cysteine/spacer region open the closed conformation in acquired TTP (PMID:12181489, PMID:30312976, PMID:34559219).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Establishing the primary sequence and modular domain architecture defined ADAMTS13 as a multidomain reprolysin-type zinc metalloprotease and predicted zymogen activation, framing all subsequent structure-function work.

    Evidence cDNA cloning, Northern blotting, and domain architecture analysis

    PMID:11557746

    Open questions at the time
    • Catalytic substrate not yet demonstrated
    • Mode of zymogen activation only inferred from furin site
  2. 2002 High

    Reconstitution with recombinant protein answered whether ADAMTS13 is itself the plasma VWF-cleaving protease, confirming identity and that TTP autoantibodies inhibit this activity.

    Evidence Recombinant ADAMTS13 in HEK293 cells, VWF multimer degradation assay, inhibition by TTP plasma

    PMID:12393399

    Open questions at the time
    • Scissile bond and physiologic activation conditions not yet defined
    • Cellular source in vivo unaddressed
  3. 2002 High

    Mutagenesis of congenital TTP alleles distinguished two disease mechanisms—impaired secretion versus reduced catalytic activity—linking specific variants to loss of function.

    Evidence Expression of mutant ADAMTS13 in HeLa cells with secretion and activity readouts

    PMID:12181489

    Open questions at the time
    • Conformational basis of dysfunction not yet known
    • Did not address acquired/autoantibody-mediated disease
  4. 2005 Medium

    Identifying hepatic stellate cells (and endothelial cells/platelets) as cellular sources answered where active ADAMTS13 originates, beyond the liver as an organ.

    Evidence In situ hybridization, cell fractionation with activity assays, RT-PCR, platelet lysate activity assays

    PMID:15806136 PMID:16176307

    Open questions at the time
    • Relative contribution of each source to plasma pool unquantified
    • Regulation of cell-type-specific expression unknown
  5. 2007 High

    Demonstrating shear- and platelet-GPIbalpha-dependent enhancement of cleavage explained how ADAMTS13 selectively trims the largest, most thrombogenic VWF multimers under physiologic flow.

    Evidence Cone-plate viscometer shear assay with anti-GPIbalpha blocking and multimeric gel analysis

    PMID:17901248

    Open questions at the time
    • Molecular mechanism of shear-induced substrate exposure not resolved here
    • Enzyme conformational change not yet linked
  6. 2007 High

    Mapping the VWF A2 N1574 glycan as a modulator of susceptibility connected substrate glycosylation (and ABO blood group) to cleavage efficiency.

    Evidence PNGase F digestion, lectin analysis, recombinant VWF-A2 mutagenesis, binding and proteolysis assays

    PMID:17975018

    Open questions at the time
    • Mechanism by which glycan shields the scissile site not structurally defined
  7. 2008 Medium

    Kinetic and thermodynamic dissection identified VWF A2 'hot spot' residues and ionizable catalytic groups, and proposed a C-shaped enzyme conformation needed to orient the scissile bond.

    Evidence FRETS kinetic assays across pH/temperature, Co2+ substitution, product inhibition, molecular modeling

    PMID:18502798

    Open questions at the time
    • Computational C-shape model not structurally validated at the time
    • Single-lab kinetic interpretation
  8. 2009 High

    Live-cell imaging established that endothelial ADAMTS13 is secreted constitutively via the Golgi and cleaves cell-anchored VWF strings, defining a local surveillance mechanism distinct from VWF storage.

    Evidence Live-cell HUVEC imaging, domain-specific blocking antibodies, VWF string cleavage assay

    PMID:19822897

    Open questions at the time
    • Quantitative contribution of endothelial vs plasma enzyme to string cleavage unclear
  9. 2010 High

    Subsite mutagenesis localized determinants of catalytic efficiency (VR1) and P1' specificity (VR3) within the metalloprotease domain, refining the active-site model.

    Evidence Domain swapping with ADAMTS1/2, site-directed mutagenesis, kinetics with VWF115

    PMID:20647566

    Open questions at the time
    • Did not address distal-domain allosteric control of these subsites
  10. 2014 High

    SAXS plus truncation kinetics revealed distal T8-CUB autoinhibition relieved by VWF D4 binding, establishing substrate-induced allosteric activation as the core regulatory logic.

    Evidence Kinetic assays with truncated variants, SAXS, monoclonal antibody domain blocking

    PMID:25512528

    Open questions at the time
    • Atomic structure of closed conformation not yet available
    • Precise distal contact residues unresolved
  11. 2019 High

    A crystal structure of the metalloprotease-to-spacer region captured the latent occluded active site and ordered the exosite engagement steps, showing VWF serves as both cofactor and substrate; complementary phylogenetic deletion work pinpointed T7/T8 as the essential allosteric switches.

    Evidence X-ray crystallography with exosite mutagenesis; domain deletion across 20 species with shear-dependent cleavage assays

    PMID:30700419 PMID:31439947

    Open questions at the time
    • Full-length closed conformation structure still lacking
    • T3-T6 function (dispensable here) unexplained
  12. 2020 High

    Kinetic dissection of antibody-induced activation showed the open conformation increases kcat without changing Km, localizing the allosteric effect to the metalloprotease active site rather than exosite exposure.

    Evidence Km/kcat kinetics, conformation ELISA, anti-spacer and anti-CUB1 monoclonal antibodies

    PMID:32196558

    Open questions at the time
    • Physiologic trigger of the cryptic-epitope exposure in vivo not defined
  13. 2017 High

    Systematic N-glycan mutagenesis showed CUB-domain glycans modulate the CUB-spacer interaction and thus the closed/open equilibrium, linking glycosylation directly to conformational regulation.

    Evidence Enzymatic glycan removal, site-directed glycan-site mutagenesis, static/shear kinetics, immunoprecipitation of CUB-spacer interaction

    PMID:28370891

    Open questions at the time
    • In vivo regulation of glycan occupancy not addressed
  14. 2018 Medium

    Conformation profiling of congenital and acquired TTP established that disease-causing mutations and anti-CS autoantibodies act by disrupting the spacer-CUB interaction that keeps ADAMTS13 folded.

    Evidence Conformation ELISA with USS genotyping; affinity-purified anti-CS/anti-CUB autoantibody fractions

    PMID:30312976 PMID:34559219

    Open questions at the time
    • Single-lab conformation assay
    • Causal link from open conformation to clinical phenotype not directly demonstrated
  15. 2012 Medium

    Cellular and Co-IP studies revealed a VWF-independent role: ADAMTS13 TSP1 repeats bind VEGF and promote endothelial proliferation, migration, and tube formation.

    Evidence Matrigel/Boyden/proliferation assays, co-immunoprecipitation, domain truncation; receptor-mediated endocytosis by mannose receptor on dendritic cells

    PMID:22289891 PMID:22626948

    Open questions at the time
    • Pro- vs anti-angiogenic effects context-dependent and unreconciled
    • In vivo relevance of TSP1-VEGF binding not shown here
  16. 2017 High

    Loss- and gain-of-function studies placed endogenous ADAMTS13 upstream of VEGF/VEGFR2/AKT signaling and defined its protective vascular roles via VWF-dependent epistasis in stroke, diabetic nephropathy, and atherosclerosis.

    Evidence siRNA knockdown in HUVEC with VEGF/AKT/VEGFR2 readouts; Adamts13-/-/Vwf-/- double/triple knockout mouse epistasis in stroke, nephropathy, and atherosclerosis models

    PMID:24261607 PMID:24950743 PMID:28428179 PMID:28495930 PMID:28546076

    Open questions at the time
    • Whether vascular protection requires proteolytic activity or TSP1-mediated signaling not always separated
    • Cell-of-origin of the relevant ADAMTS13 in vivo unclear
  17. 2019 Medium

    Studies in placenta, cardiomyocytes, Alzheimer's models, and allografts extended ADAMTS13 function to trophoblast invasion, inhibition of TSP1-induced CaMKII signaling, blood-brain barrier maintenance/Abeta clearance, and reduction of NET formation.

    Evidence Knockdown/recombinant protein in trophoblasts; Adamts13-/- diabetic heart and APPPS1 brain models with viral rescue; murine skin allograft NET imaging

    PMID:28751574 PMID:29976618 PMID:31185010 PMID:31730284

    Open questions at the time
    • Molecular substrates/partners in these tissues largely undefined
    • Single-lab models for each novel function
    • Dependence on metalloprotease activity vs TSP1 signaling not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the physiologic open-conformation trigger, glycosylation state, and tissue-specific non-VWF functions are integrated and regulated in vivo remains unresolved.
  • No full-length closed-conformation structure
  • Substrates for non-VWF/TSP1-mediated functions unidentified
  • Endogenous activators of the conformational switch in vivo undefined

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 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-109582 Hemostasis 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
GP1BAMRC1THBS1VEGFAVWF

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ADAMTS13 (VWFCP) is a 1427-amino-acid metalloprotease with a domain architecture comprising: signal peptide, short propeptide (ending in RQRR furin cleavage site), reprolysin-like metalloprotease domain, disintegrin-like domain, thrombospondin-1 repeat, Cys-rich domain, spacer domain, seven additional TSP1 repeats, and two CUB domains. The protein contains conserved Zn2+ and Ca2+ binding sites in the protease domain. Northern blotting detected full-length mRNA only in liver. The protein is apparently synthesized as a zymogen requiring proteolytic activation, possibly by furin. cDNA cloning, Northern blotting, domain architecture analysis The Journal of biological chemistry High 11557746
2002 Recombinant ADAMTS13 expressed in HEK293 cells degrades VWF multimers and proteolytically cleaves VWF to the same fragments generated by plasma VWF-cleaving protease, confirming ADAMTS13 is the physiologic VWF-cleaving metalloprotease. Recombinant ADAMTS13-mediated VWF degradation was entirely inhibited by plasma from an acquired TTP patient (containing inhibitory autoantibodies). Expression of recombinant ADAMTS13 in HEK293 cells, VWF multimer degradation assay, inhibition by TTP patient plasma Blood High 12393399
2002 Missense mutations R268P and C508Y in ADAMTS13 abolish enzyme activity by preventing secretion from cells. Nonsense mutation Q449stop and missense P475S produce secreted protein with minimal or reduced activity respectively, demonstrating that defects in both protein secretion and catalytic activity are mechanisms underlying congenital TTP. Expression analysis of mutant ADAMTS13 in HeLa cells, activity assays, secretion analysis Proceedings of the National Academy of Sciences of the United States of America High 12181489
2005 ADAMTS13 is expressed primarily by hepatic stellate cells in the liver. In situ hybridization, cell fractionation with proteolytic activity measurement in conditioned media, and RT-PCR of isolated hepatic stellate cells all identified this cell type as the primary hepatic source. Mouse ADAMTS13 cloned from hepatic stellate cells was active against VWF and inhibited by EDTA or TTP patient IgG inhibitors. In situ hybridization, cell fractionation with activity assays, RT-PCR, cloning from primary hepatic stellate cells Laboratory investigation; a journal of technical methods and pathology High 15806136
2007 ADAMTS13 preferentially cleaves platelet-VWF complexes under fluid shear stress. Platelet-dependent cleavage was blocked by anti-GPIbalpha monoclonal antibody or soluble GPIbalpha fragment, demonstrating that platelet binding to VWF via GPIbalpha is required for this enhanced proteolysis. Shear and platelet-dependent cleavage preferentially consumed large VWF multimers. Cone-plate viscometer shear assay, blocking antibodies against GPIbalpha, multimeric gel analysis Blood High 17901248
2009 ADAMTS13 is released constitutively from endothelial cells directly from the Golgi to the cell exterior, without storage in an organelle (unlike VWF which is stored in Weibel-Palade bodies). HUVEC-released ADAMTS13 cleaves secreted and cell-anchored VWF strings at the Y1605-M1606 bond within 15 minutes. Blocking antibodies against different ADAMTS13 domains detected ADAMTS13 attachment along the lengths of VWF strings on the endothelial surface. Live-cell imaging of HUVEC, immunofluorescence with domain-specific antibodies, VWF cleavage assay under static conditions Blood High 19822897
2010 Two subsites in the ADAMTS13 metalloprotease domain are critical for function: VR1 (D187-R193) contains residues D187, R190, and R193 that influence cleavage efficiency (point mutants reduce kcat/Km 2-10 fold); VR3 residues D252-P256 influence P1' amino acid specificity, shaping the S1' substrate-binding pocket. Domain swapping between ADAMTS13 and ADAMTS1/2, site-directed mutagenesis, kinetic analysis with VWF115 substrate Blood High 20647566
2007 N-linked glycan at position N1574 in the VWF A2 domain modulates ADAMTS13 interaction; mutation of N1574 increased VWF susceptibility to ADAMTS13 proteolysis and allowed cleavage in the absence of urea. N1515 mutation did not alter ADAMTS13 binding or proteolysis rate. ABO blood group sugars are presented on N-linked glycans at N1515 and N1574. PNGase F digestion, lectin analysis, recombinant VWF mutagenesis, binding and proteolysis assays with isolated VWF-A2 domain Blood High 17975018
2014 The distal T8-CUB2 domains of ADAMTS13 markedly inhibit substrate cleavage (autoinhibition). Binding of VWF (specifically the D4 domain) or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering demonstrated that distal T-CUB domains physically interact with proximal MDTCS domains in the resting state, supporting substrate-induced allosteric activation. Kinetic assays with truncated ADAMTS13 variants, SAXS, monoclonal antibody-mediated domain blocking 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 the metalloprotease domain in a latent conformation with an occluded active-site cleft. Kinetic analyses showed that binding of the ADAMTS13 cysteine-rich and spacer domain exosites to VWF brings enzyme and substrate into proximity, then binding of the disintegrin-like domain exosite to VWF allosterically activates the adjacent metalloprotease domain by opening the active-site cleft. VWF thus functions as both the activating cofactor and substrate for ADAMTS13. X-ray crystallography, kinetic analysis, exosite mutagenesis Nature communications High 31439947
2019 T7 and T8 distal domains of ADAMTS13 are essential for allosteric activation by VWF; deletion of either T7 or T8 abolished allosteric activation. In contrast, T3-T6 domains are dispensable: pigeon ADAMTS13 with only 3 distal T domains retained normal allosteric regulation and shear-dependent VWF cleavage. Human ADAMTS13 engineered to resemble pigeon ADAMTS13 (lacking T3-T6) retained normal allosteric regulation. Phylogenetic analysis, domain deletion variants, kinetic assays across 20 mammalian/avian/amphibian species, shear-dependent cleavage assays Blood High 30700419
2020 Antibody-induced conformational activation of ADAMTS13 (from closed/folded to open conformation) enhances ADAMTS13 proteolytic function by increasing kcat (turnover), not by augmenting substrate binding (Km unchanged). This mechanism is allosteric, acting on the metalloprotease domain active site, not via exposure of cysteine-rich or spacer domain exosites. Conformational extension exposes a cryptic epitope in the metalloprotease domain that is normally concealed in the closed conformation. Kinetic analysis (Km, kcat, kcat/Km), conformation ELISA, domain-specific monoclonal antibodies (anti-Spacer 3E4, anti-CUB1 17G2) Blood advances High 32196558
2008 ADAMTS13 catalysis of Tyr1605-Met1606 bond hydrolysis in VWF is governed by two ionizable groups (pKa 6.41 and ~4.0). The transition state has negative activation entropy, indicating an ordered transition state. The VWF Met1606-Arg1668 product acts as a hyperbolic mixed-type inhibitor. Residues Asp1653, Glu1655, Glu1660, Asp1663, and Thr1656 in VWF A2 form a 'hot spot' driving molecular recognition by ADAMTS13. A molecular model indicates ADAMTS13 must adopt a C-like shape to accommodate substrate and properly orient the scissile bond. Fluorescence quenching (FRETS) kinetic assays across temperature and pH ranges, Co2+ substitution, product inhibition analysis, molecular modeling Biophysical journal Medium 18502798
2005 ADAMTS13 is also synthesized and secreted by vascular endothelial cells, and platelet lysates contain functionally active ADAMTS13 that cleaves endothelial cell-derived ultra-large VWF under static and flow conditions. Platelet surface ADAMTS13 expression increases upon activation by thrombin receptor-activating peptide but not ADP. The platelet-derived ADAMTS13 activity is inhibited by EDTA and by TTP patient anti-ADAMTS13 IgG. ADAMTS13 activity assay in platelet lysates, anti-ADAMTS13 antibody blocking, flow-based VWF cleavage assay, platelet activation assays Journal of thrombosis and haemostasis : JTH Medium 16176307
2010 Biologically active ADAMTS13 is expressed and secreted by human renal tubular epithelial cells (primary HRTEC and A498 cell line), demonstrated by RT-PCR, immunofluorescence, immunoblotting, and proteolytic cleavage of FRETS-VWF73 substrate. ADAMTS13 was also detected in situ in proximal and distal renal tubules in normal human kidney and was present in urine of patients with tubulopathy (but not normal urine), indicating the protease originates in tubuli. Real-time PCR, immunofluorescence, immunoblotting, FRETS-VWF73 substrate cleavage assay, immunohistochemistry, urine analysis Pediatric nephrology (Berlin, Germany) Medium 19644711
2011 Human glomerular endothelial cells express, secrete, and produce functionally active ADAMTS13, demonstrated by real-time PCR, flow cytometry, immunofluorescence, immunoblotting, and VWF cleavage assays. ADAMTS13-deficient mice showed thickening of glomerular capillaries with platelet deposition on vessel walls, indicating ADAMTS13 protects against glomerular platelet deposition. RT-PCR, flow cytometry, immunofluorescence, immunoblotting, VWF cleavage assay, immunohistochemistry of Adamts13-/- vs wild-type mouse kidneys PloS one Medium 21720563
2010 Thrombospondin-1 (TSP1) competitively inhibits ADAMTS13 binding and cleavage of VWF by binding to VWF A2 and A3 domains. TSP1 partially blocked ADAMTS13 binding to A2 and A3 domains and full-length VWF, and inhibited ADAMTS13 activity by up to 70% in vitro. ELISA-based binding assay with recombinant VWF A1/A2/A3 domains, western blot, residual collagen binding assay for ADAMTS13 activity Thrombosis research Medium 20705333
2012 ADAMTS13 is endocytosed by immature monocyte-derived dendritic cells via the macrophage mannose receptor (MR). Endocytosis was blocked by EGTA (Ca2+-dependent), mannan (competing mannose sugar), and an anti-MR blocking monoclonal antibody. siRNA silencing of MR reduced ADAMTS13 uptake. In vitro binding studies confirmed interaction between ADAMTS13 sugar moieties and the carbohydrate recognition domains of MR. Flow cytometry, confocal microscopy, siRNA knockdown of MR, in vitro binding assays Blood High 22289891
2012 Recombinant ADAMTS13 promotes endothelial cell tube formation, proliferation, and migration in a dose-dependent manner. ADAMTS13 inhibits VEGF-induced angiogenesis, and this inhibitory effect is reversed by antibody against ADAMTS13 TSP1 domains 5-7. Truncated ADAMTS13 lacking the C-terminal TSP1 domain failed to stimulate angiogenesis. Co-immunoprecipitation demonstrated that ADAMTS13 binds VEGF via its TSP1 domain. Matrigel tube formation assay, proliferation counting assay, Boyden chamber migration assay, co-immunoprecipitation, domain truncation analysis Microvascular research Medium 22626948
2014 ADAMTS13 modulates atherosclerotic plaque progression through a VWF-dependent mechanism. Triple knockout Adamts13-/-/Vwf-/-/ApoE-/- mice showed complete reversal of exacerbated atherosclerosis seen in Adamts13-/-/ApoE-/- mice, with lesion size, macrophage and neutrophil infiltration, and collagen content reduced to levels seen in Vwf-/-/ApoE-/- mice. Genetic epistasis using triple knockout mice, histological analysis, immunohistochemistry for macrophages and neutrophils, picrosirius red staining for collagen Journal of thrombosis and haemostasis : JTH High 24261607
2014 ADAMTS13 TSP1 repeats (specifically TSP1 2-8) are required for its pro-angiogenic effects; variants containing TSP1 2-8 repeats increased HUVEC proliferation, migration, and VEGFR2 phosphorylation. ADAMTS13 induces VEGF expression (53% increase at protein level, >6-fold increase in mRNA) within 10 minutes. Anti-VEGF IgG abrogated ADAMTS13-enhanced proliferation, migration, and VEGFR2 phosphorylation. Structure-function analysis with ADAMTS13 truncation variants, ELISA, Western blot for VEGF and phospho-VEGFR2, proliferation and chemotaxis assays, anti-VEGF blocking Cellular and molecular life sciences : CMLS Medium 24950743
2007 In endotoxemia mice, ADAMTS13 plasma activity is decreased within 2 hours of LPS injection. Pretreatment with a neutrophil elastase inhibitor or use of plasminogen-deficient mice prevented the decrease in ADAMTS13 activity, demonstrating that both plasmin and neutrophil elastase coordinately degrade/inactivate ADAMTS13 in endotoxinemia. LPS injection in mice, pharmacological neutrophil elastase inhibitor pretreatment, plasminogen-deficient mouse model, ADAMTS13 activity assays Thrombosis research Medium 18006046
2017 ADAMTS13 deficiency impairs post-stroke neovascularization; Adamts13-/- mice showed reduced microvessels, brain capillary perfusion, pericyte coverage, and accelerated BBB breakdown after stroke. These vascular defects were reversed by VWF deficiency or anti-VWF antibody in Adamts13-/- mice. ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 in brain microvessels; VWF deficiency had the opposite effect. Recombinant ADAMTS13 treatment at 7 days post-stroke increased neovascularization and improved functional recovery. Adamts13-/- and Vwf-/- mouse stroke model, intravital microscopy, histology, recombinant ADAMTS13 treatment, adenovirus angiopoietin-2 overexpression, VEGFR2 antagonist (SU1498) Blood High 28428179
2017 ADAMTS13 is expressed in human placenta, primarily in trophoblasts and villous core fetal vessel endothelium, and is proteolytically active. Placental ADAMTS13 expression is highest in the first trimester and significantly reduced under hypoxic conditions and in preeclampsia. Recombinant ADAMTS13 stimulates proliferation, migration, invasion, and network formation of trophoblastic cells; knockdown of ADAMTS13 attenuates tube formation in trophoblast cells and extravillous trophoblast outgrowth in placental explants. RT-PCR, immunohistochemistry, Western blot, FRETS-VWF73 activity assay, MTT assay, wound scratch assay, transwell migration assay, tube formation assay, tissue outgrowth assay, ADAMTS13 knockdown Arteriosclerosis, thrombosis, and vascular biology Medium 28751574
2017 ADAMTS13 deficiency in diabetic mice promotes ventricular arrhythmias through aberrant connexin 43 distribution and increased CaMKII phosphorylation in cardiomyocytes. Thrombospondin-1 (TSP1) promotes CaMKII phosphorylation in cardiomyocytes in a paracrine manner, and ADAMTS13 acts to inhibit TSP1-induced CaMKII activation in vitro. Streptozotocin-induced diabetes in Adamts13-/- mice, dobutamine stress testing, connexin 43 immunolocalization, CaMKII phosphorylation assays, in vitro HL-1 cardiomyocyte TSP1/ADAMTS13 treatment Diabetes Medium 29976618
2018 Recombinant ADAMTS13 treatment reduces NET burden in skin allografts and prolongs allograft survival in mice. Western blot and immunofluorescence microscopy showed NETs in allografts of vehicle-treated but not rhADAMTS13-treated mice 3 days post-surgery, identifying a novel mechanism of ADAMTS13 action in reducing neutrophil extracellular trap formation. Murine skin allograft model, immunofluorescence microscopy, Western blot for NETs, recombinant ADAMTS13 treatment American journal of transplantation Medium 31730284
2017 N-linked glycans of ADAMTS13 regulate its activity. Terminal sialic acid removal from metalloprotease domain glycans decreases ADAMTS13 activity. CUB domain glycan mutations (N1235Q and N1354Q) enhanced activity against both FRETS-VWF73 and VWF under shear, and reduced the CUB-spacer domain interaction (assessed by immunoprecipitation), confirming that CUB domain glycans modulate the closed/open conformational equilibrium. TSP2 domain glycan mutation (N707Q) reduced static but not flow activity. Enzymatic glycan removal, site-directed mutagenesis of N-linked glycan sites, kinetic assays under static and shear conditions, immunoprecipitation of CUB-spacer interaction Journal of thrombosis and haemostasis : JTH High 28370891
2018 In congenital TTP (Upshaw-Schulman syndrome), ADAMTS13 gene mutations alter ADAMTS13 conformation, with 87.5% of examined patients exhibiting abnormalities of ADAMTS13 conformation. Adult-onset USS is predominantly associated with the p.Arg1060Trp mutation (in 82% of adult-onset patients), suggesting this specific variant preferentially disrupts the spacer-CUB interaction that maintains ADAMTS13 in its folded conformation. ADAMTS13 conformation ELISA, genotyping of 56 USS patients, correlation of genotype with conformation Thrombosis and haemostasis Medium 30312976
2021 Anti-cysteine/spacer (CS) domain autoantibodies from iTTP patients can disrupt the spacer-CUB interaction of folded ADAMTS13 (open its conformation). All purified anti-CS fractions from 10/10 patients tested were able to open ADAMTS13, while only 2/4 anti-CUB fractions opened ADAMTS13, establishing the anti-CS antibodies' mechanism of action as disrupting closed conformation. Affinity chromatography purification of anti-CS and anti-CUB autoantibody fractions, ADAMTS13 conformation ELISA Blood advances Medium 34559219
2017 siRNA knockdown of endogenous ADAMTS13 in HUVEC reduced proliferation by 21%, abolished scratch wound migration, and decreased tube formation (tube length, size, junction numbers) by ~40%. ADAMTS13 knockdown decreased VEGF protein by 45% and downregulated AKT pathway activity, placing endogenous ADAMTS13 upstream of VEGF/AKT signaling in endothelial angiogenesis. siRNA knockdown of ADAMTS13 in HUVEC, proliferation assay, scratch wound assay, Matrigel tube formation assay, Western blot for VEGF and phospho-AKT Microvascular research Medium 28546076
2019 ADAMTS13 deficiency in APP/PS1 Alzheimer's disease mice caused progressive blood-brain barrier breakdown, reduced vessel density, capillary perfusion, and cerebral blood flow, and accelerated Aβ accumulation. Viral-mediated ADAMTS13 expression in APPPS1 mice with established pathology attenuated BBB disruption, increased microvascular perfusion, increased BBB-mediated Aβ clearance, reduced plaque load, and improved cognitive performance. In vivo multiphoton microscopy, histological analysis, behavioral testing, viral vector ADAMTS13 overexpression in Adamts13-/-/APPPS1 mice PLoS biology Medium 31185010
2017 ADAMTS13 deficiency exacerbates diabetic nephropathy through VWF-dependent intrarenal thrombosis. Adamts13-/- diabetic mice had worse kidney function and more intrarenal thrombosis than WT diabetic mice; genetic deletion of VWF in Adamts13-/- diabetic mice improved kidney function and inhibited intrarenal thrombosis, demonstrating that ADAMTS13 protects against diabetic nephropathy by inhibiting VWF-dependent thrombosis. Streptozotocin diabetic mouse model in Adamts13-/-, Vwf-/-, and Adamts13-/-Vwf-/- mice, renal function measurements, immunohistochemistry for thrombosis markers Arteriosclerosis, thrombosis, and vascular biology High 28495930

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 672 11557746
2002 Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proceedings of the National Academy of Sciences of the United States of America 324 12181489
2011 Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 236 21715306
2015 ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annual review of medicine 192 25587650
2002 Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 190 12393399
2020 The ADAMTS13-von Willebrand factor axis in COVID-19 patients. Journal of thrombosis and haemostasis : JTH 175 33230904
2011 Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. Journal of thrombosis and haemostasis : JTH 153 21781265
2005 ADAMTS13 is expressed in hepatic stellate cells. Laboratory investigation; a journal of technical methods and pathology 142 15806136
2010 ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Human mutation 138 19847791
2007 Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 132 17901248
2006 ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. Blood 109 17053057
2013 Structure-function and regulation of ADAMTS-13 protease. Journal of thrombosis and haemostasis : JTH 105 23809107
2009 Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 104 19822897
2014 Allosteric activation of ADAMTS13 by von Willebrand factor. Proceedings of the National Academy of Sciences of the United States of America 103 25512528
2017 ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery. Blood 94 28428179
2020 Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13. Frontiers in immunology 90 33343584
2005 Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. Journal of thrombosis and haemostasis : JTH 86 16176307
2021 Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis. Seminars in thrombosis and hemostasis 81 33893632
2007 N-linked glycosylation of VWF modulates its interaction with ADAMTS13. Blood 81 17975018
2019 Crystal structure and substrate-induced activation of ADAMTS13. Nature communications 71 31439947
2004 von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Seminars in hematology 71 14727254
2002 ADAMTS13 and TTP. Current opinion in hematology 65 12172456
2021 ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. Journal of thrombosis and haemostasis : JTH 60 34053187
2010 The balance between von-Willebrand factor and its cleaving protease ADAMTS13: biomarker in systemic inflammation and development of organ failure? Current molecular medicine 59 20196724
2016 Von Willebrand Factor, ADAMTS13, and the Risk of Mortality: The Rotterdam Study. Arteriosclerosis, thrombosis, and vascular biology 57 27737864
2012 Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Hematology. American Society of Hematology. Education Program 57 23233642
2018 ADAMTS13 Gene Mutations Influence ADAMTS13 Conformation and Disease Age-Onset in the French Cohort of Upshaw-Schulman Syndrome. Thrombosis and haemostasis 53 30312976
2013 Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. Hematology (Amsterdam, Netherlands) 48 23433535
2012 ADAMTS13 promotes angiogenesis and modulates VEGF-induced angiogenesis. Microvascular research 43 22626948
2012 The macrophage mannose receptor promotes uptake of ADAMTS13 by dendritic cells. Blood 42 22289891
2022 Mechanisms of ADAMTS13 regulation. Journal of thrombosis and haemostasis : JTH 40 36074019
2019 Synergistic effects of ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy. Blood 39 31409673
2018 Role of CD40 and ADAMTS13 in von Willebrand factor-mediated endothelial cell-platelet-monocyte interaction. Proceedings of the National Academy of Sciences of the United States of America 39 29793936
2012 ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 39 22212812
2010 Thrombospondin-1 and ADAMTS13 competitively bind to VWF A2 and A3 domains in vitro. Thrombosis research 39 20705333
2020 Antibodies that conformationally activate ADAMTS13 allosterically enhance metalloprotease domain function. Blood advances 38 32196558
2019 The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension. The European respiratory journal 38 30655285
2008 Thrombotic thrombocytopenic purpura related to severe ADAMTS13 deficiency in children. Pediatric nephrology (Berlin, Germany) 38 18574602
2002 Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Journal of molecular medicine (Berlin, Germany) 38 12395148
2021 Laboratory testing for ADAMTS13: Utility for TTP diagnosis/exclusion and beyond. American journal of hematology 36 33991361
2010 The ADAMTS13 metalloprotease domain: roles of subsites in enzyme activity and specificity. Blood 36 20647566
2018 ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function. American journal of physiology. Renal physiology 34 30461292
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
2005 Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. Seminars in thrombosis and hemostasis 33 16388417
2019 Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis. Journal of thrombosis and haemostasis : JTH 32 31758651
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
2004 Assays of ADAMTS-13 activity. Seminars in hematology 32 14727258
2017 Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development. Arteriosclerosis, thrombosis, and vascular biology 30 28751574
2014 ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2. Cellular and molecular life sciences : CMLS 30 24950743
2018 Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality After Pressure Overload Injury in Mice. Journal of the American Heart Association 29 29367415
2005 Pathogenesis of thrombotic thrombocytopenic purpura: ADAMTS13 deficiency and beyond. Seminars in thrombosis and hemostasis 29 16388413
2019 ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology. PLoS biology 28 31185010
2019 VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma. BMC gastroenterology 28 31638892
2018 ADAMTS13: origins, applications, and prospects. Transfusion 28 30208220
2018 Anti-ADAMTS13 Autoantibodies against Cryptic Epitopes in Immune-Mediated Thrombotic Thrombocytopenic Purpura. Thrombosis and haemostasis 28 30235483
2019 Phylogenetic and functional analysis of ADAMTS13 identifies highly conserved domains essential for allosteric regulation. Blood 27 30700419
2015 ADAMTS13 and anti-ADAMTS13 autoantibodies in thrombotic thrombocytopenic purpura - current perspectives and new treatment strategies. Expert review of hematology 27 26581428
2021 Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis. Blood advances 26 34505883
2014 Inherited ADAMTS13 deficiency (Upshaw-Schulman syndrome): a short review. Thrombosis research 26 25242241
2004 Expression and characterization of recombinant human ADAMTS-13. Seminars in hematology 26 14727256
2017 Plasma ADAMTS13 activity and von Willebrand factor antigen and activity in patients with subarachnoid haemorrhage. Thrombosis and haemostasis 25 28102428
2010 Biologically active ADAMTS13 is expressed in renal tubular epithelial cells. Pediatric nephrology (Berlin, Germany) 25 19644711
2017 ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice. Arteriosclerosis, thrombosis, and vascular biology 24 28495930
2016 Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies. Immunobiology 24 27771173
2005 Interplay between ADAMTS13 and von Willebrand factor in inherited and acquired thrombotic microangiopathies. Seminars in hematology 23 15662617
2022 The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer. Healthcare (Basel, Switzerland) 22 35327035
2016 ADAMTS13: more than a regulator of thrombosis. International journal of hematology 22 27696191
2008 Mechanistic studies on ADAMTS13 catalysis. Biophysical journal 22 18502798
2021 Characterization of ADAMTS13 and von Willebrand factor levels in septic and non-septic ICU patients. PloS one 21 33606732
2011 Phenotypic expression of ADAMTS13 in glomerular endothelial cells. PloS one 21 21720563
2006 ADAMTS13 and microvascular thrombosis. Expert review of cardiovascular therapy 21 17173498
2005 Transcriptional regulation of ADAMTS13. Thrombosis and haemostasis 20 16113782
2020 ADAMTS13 ameliorates inflammatory responses in experimental autoimmune encephalomyelitis. Journal of neuroinflammation 19 32075652
2018 mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice. Scientific reports 19 29777164
2024 ADAMTS13 in the New Era of TTP. International journal of molecular sciences 18 39125707
2022 Evidence of protective effects of recombinant ADAMTS13 in a humanized model of sickle cell disease. Haematologica 18 35443560
2020 ADAMTS13 activity, high VWF and FVIII levels in the pathogenesis of deep vein thrombosis. Thrombosis research 18 33212380
2020 ADAMTS13 inhibits oxidative stress and ameliorates progressive chronic kidney disease following ischaemia/reperfusion injury. Acta physiologica (Oxford, England) 18 33226724
2019 Recombinant human ADAMTS13 treatment and anti-NET strategies enhance skin allograft survival in mice. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 17 31730284
2013 Proteolytic processing of von Willebrand factor by adamts13 and leukocyte proteases. Mediterranean journal of hematology and infectious diseases 17 24106608
2018 Insights into 3D Structure of ADAMTS13: A Stepping Stone towards Novel Therapeutic Treatment of Thrombotic Thrombocytopenic Purpura. Thrombosis and haemostasis 16 29304523
2021 Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP. Blood advances 15 34559219
2015 ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor-Induced Thrombotic Microangiopathy. Journal of the American Society of Nephrology : JASN 14 26038528
2013 ADAMTS13 activity and genetic mutations in Japan. Hamostaseologie 14 23715102
2023 ADAMTS13 and Non-ADAMTS13 Biomarkers in Immune-Mediated Thrombotic Thrombocytopenic Purpura. Journal of clinical medicine 13 37834813
2020 Generation and validation of small ADAMTS13 fragments for epitope mapping of anti-ADAMTS13 autoantibodies in immune-mediated thrombotic thrombocytopenic purpura. Research and practice in thrombosis and haemostasis 13 32685903
2007 Unbalanced expression of ADAMTS13 and von Willebrand factor in mouse endotoxinemia. Thrombosis research 13 18006046
2005 VWF-cleaving protease (ADAMTS13) in premature infants. Acta paediatrica (Oslo, Norway : 1992) 13 15981755
2020 Current and Future Perspectives on ADAMTS13 and Thrombotic Thrombocytopenic Purpura. Hamostaseologie 12 32726827
2019 Von Willebrand Factor Adhesive Activity and ADAMTS13 Protease Activity in HIV-1-Infected Men. International journal of medical sciences 12 30745808
2017 ADAMTS-13 glycans and conformation-dependent activity. Journal of thrombosis and haemostasis : JTH 12 28370891
2011 Structure and proteolytic properties of ADAMTS13, a metalloprotease involved in the pathogenesis of thrombotic microangiopathies. Progress in molecular biology and translational science 12 21238935
2022 From the Discovery of ADAMTS13 to Current Understanding of Its Role in Health and Disease. Seminars in thrombosis and hemostasis 11 36368692
2021 The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease. Journal of cardiovascular development and disease 11 34564132
2018 ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental Diabetes. Diabetes 11 29976618
2017 siRNA-knockdown of ADAMTS-13 modulates endothelial cell angiogenesis. Microvascular research 11 28546076
2014 Interactions of von Willebrand factor and ADAMTS13 in von Willebrand disease and thrombotic thrombocytopenic purpura. Hamostaseologie 11 25010251
2025 ADAMTS13 Improves Endothelial Function and Reduces Inflammation in Diabetic Retinopathy. Cells 10 39851513

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