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Article ; Online: Current and Future Perspectives on ADAMTS13 and Thrombotic Thrombocytopenic Purpura.

Roose, Elien / Joly, Bérangère S

2020 Volume 40, Issue 3, Page(s) 322–336

Abstract: Thrombotic thrombocytopenic purpura (TTP) is a rare, relapsing, and life-threatening disorder with an annual incidence of 10 cases per million people. TTP is a thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic ... ...

Abstract	Thrombotic thrombocytopenic purpura (TTP) is a rare, relapsing, and life-threatening disorder with an annual incidence of 10 cases per million people. TTP is a thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. The disease is caused by a severe deficiency of the enzyme ADAMTS13 (
MeSH term(s)	ADAMTS13 Protein/deficiency ; ADAMTS13 Protein/genetics ; ADAMTS13 Protein/therapeutic use ; Anemia, Hemolytic/diagnosis ; Anemia, Hemolytic/etiology ; Animals ; Autoantibodies/immunology ; Autoantibodies/metabolism ; Diagnosis, Differential ; Female ; Humans ; Immunologic Factors/therapeutic use ; Incidence ; Male ; Mice ; Molecular Targeted Therapy/methods ; Mutation ; Plasma Exchange/adverse effects ; Plasma Exchange/methods ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Purpura, Thrombotic Thrombocytopenic/enzymology ; Purpura, Thrombotic Thrombocytopenic/epidemiology ; Purpura, Thrombotic Thrombocytopenic/therapy ; Quality of Life ; Recombinant Proteins/therapeutic use ; Rituximab/therapeutic use ; Single-Domain Antibodies/therapeutic use ; Thrombocytopenia/diagnosis ; Thrombocytopenia/etiology
Chemical Substances	Autoantibodies ; Immunologic Factors ; Recombinant Proteins ; Single-Domain Antibodies ; caplacizumab (2R27AB6766) ; Rituximab (4F4X42SYQ6) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2020-07-29
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	801512-0
ISSN	2567-5761 ; 0720-9355
ISSN (online)	2567-5761
ISSN	0720-9355
DOI	10.1055/a-1171-0473
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Article ; Online: ADAMTS13 conformation is closed in non-immune acquired thrombotic thrombocytopenic purpura of unidentified pathophysiology.

Joly, Bérangère S / Roose, Elien / Coppo, Paul / Vanhoorelbeke, Karen / Veyradier, Agnès

Haematologica

2023 Volume 108, Issue 2, Page(s) 638–644

MeSH term(s)	Humans ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Autoantibodies ; ADAM Proteins ; ADAMTS13 Protein
Chemical Substances	Autoantibodies ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2023-02-01
Publishing country	Italy
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.280768
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Article ; Online: Insights into ADAMTS13 structure: impact on thrombotic thrombocytopenic purpura diagnosis and management.

Roose, Elien / Veyradier, Agnès / Vanhoorelbeke, Karen

Current opinion in hematology

2020 Volume 27, Issue 5, Page(s) 320–326

Abstract: Purpose of review: Fundamental knowledge on the role of a disintegrin and metalloprotease with thrombospondin type one repeats, member 13 (ADAMTS13) has been crucial to better understand the pathophysiology of the rare and life-threatening disease ... ...

Abstract	Purpose of review: Fundamental knowledge on the role of a disintegrin and metalloprotease with thrombospondin type one repeats, member 13 (ADAMTS13) has been crucial to better understand the pathophysiology of the rare and life-threatening disease thrombotic thrombocytopenic purpura (TTP). Recent findings: ADAMTS13 works through a molecular zipper mechanism to proteolyze its substrate von Willebrand factor (VWF). Recent insights into the structure and function of ADAMTS13 led to the identification of an allosteric activation mechanism. Therefore, ADAMTS13 is roughly folded in two in which the N-terminal spacer (S) domain and C-terminal T7-CUB2 domains interact to adopt a closed conformation. Upon substrate binding, ADAMTS13 adopts an open conformation in which the S-T7-CUB2 interaction is abrogated to further position VWF towards the catalytic cleft, inducing activation of the latent metalloprotease domain and resulting in cleavage of VWF. Unravelling the structure function relationship of ADAMTS13 helped identifying open ADAMTS13 as a novel and unique biomarker for immune-mediated TTP (iTTP). This novel biomarker has potential in the diagnosis, treatment and follow-up of iTTP. Summary: In this review, the most recent findings on the structure and working mechanism of ADAMTS13 are addressed. In addition, how those findings led to the identification of a novel biomarker, and how this novel biomarker could have an impact on the diagnosis, management and follow-up of iTTP patients are discussed.
MeSH term(s)	ADAMTS13 Protein/metabolism ; Female ; Humans ; Purpura, Thrombotic Thrombocytopenic/diagnosis ; Purpura, Thrombotic Thrombocytopenic/therapy
Chemical Substances	ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2020-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000602
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Article: Current and Future Perspectives on ADAMTS13 and Thrombotic Thrombocytopenic Purpura

Roose, Elien / Joly, Bérangère S.

Hämostaseologie

2020 Volume 40, Issue 03, Page(s) 322–336

Abstract	Thrombotic thrombocytopenic purpura (TTP) is a rare, relapsing, and life-threatening disorder with an annual incidence of 10 cases per million people. TTP is a thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. The disease is caused by a severe deficiency of the enzyme ADAMTS13 ( a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 ), which can either be acquired, mainly by autoantibodies targeting ADAMTS13, or congenital due to mutations in the ADAMTS13 gene. Thanks to the establishment of national registries worldwide, fundamental and translational research, major advances have been made on the diagnosis, treatment, and fundamental understanding of TTP, since the description of the first TTP case almost 100 years ago. The introduction of therapeutic plasma exchange in the 1970s has significantly improved patient survival, but novel diagnostic assays, targeted treatments (rituximab, caplacizumab, recombinant ADAMTS13), and the unraveling of both ADAMTS13 function and TTP pathophysiology should help to further improve the patients' quality of life. However, differential diagnosis of TTP remains challenging and still a lot of questions remain unanswered to completely understand this rare and devastating disease.
Keywords	ADAMTS13 ; thrombotic thrombocytopenic purpura ; treatment ; diagnosis
Language	English
Publishing date	2020-07-29
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	801512-0
ISSN	2567-5761 ; 0720-9355
ISSN (online)	2567-5761
ISSN	0720-9355
DOI	10.1055/a-1171-0473
Database	Thieme publisher's database

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Article ; Online: Toward gene therapy for congenital thrombotic thrombocytopenic purpura.

Dekimpe, Charlotte / Roose, Elien / Sakai, Kazuya / Tersteeg, Claudia / De Meyer, Simon F / Vanhoorelbeke, Karen

Journal of thrombosis and haemostasis : JTH

2022 Volume 21, Issue 5, Page(s) 1090–1099

Abstract: Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe deficiency in the plasma metalloprotease ADAMTS-13. The current management of cTTP is dependent on the prophylactic administration of ADAMTS-13 via plasma infusion. This is a ... ...

Abstract	Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe deficiency in the plasma metalloprotease ADAMTS-13. The current management of cTTP is dependent on the prophylactic administration of ADAMTS-13 via plasma infusion. This is a demanding therapy for patients because transfusions are lifelong and time-consuming and allergic reactions frequently occur. Although current management of cTTP controls acute episodes, it does not provide a long-lasting cure for this disease. The endogenous expression of ADAMTS-13 after gene transfer would provide a curative therapy and ongoing research explores various preclinical gene therapeutic approaches for cTTP. This review focuses on the current state of the literature regarding preclinical gene therapy studies for cTTP and on the challenges of developing a gene therapy medicinal product for cTTP.
MeSH term(s)	Humans ; Purpura, Thrombotic Thrombocytopenic/genetics ; Purpura, Thrombotic Thrombocytopenic/therapy ; ADAMTS13 Protein ; Plasma ; Blood Transfusion ; Genetic Therapy/adverse effects
Chemical Substances	ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2022-12-27
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2022.12.018
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Article ; Online: Hemophagocytic lymphohistiocytosis is associated with deficiency and closed conformation of ADAMTS-13.

Launois, Amélie / Valade, Sandrine / Mariotte, Eric / Galicier, Lionel / Azoulay, Elie / Roose, Elien / Vanhoorelbeke, Karen / Veyradier, Agnès / Joly, Bérangère S

Research and practice in thrombosis and haemostasis

2023 Volume 8, Issue 1, Page(s) 102292

Abstract: Background: A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS-13) is the specific von Willebrand factor-cleaving protease and circulates in a closed and latent conformation due to a spacer/CUB1 domain interaction. ... ...

Abstract	Background: A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS-13) is the specific von Willebrand factor-cleaving protease and circulates in a closed and latent conformation due to a spacer/CUB1 domain interaction. ADAMTS-13 is allosterically activated after binding of its substrate or antibodies, inducing an open conformation. Recently, we suggested a potential role of plasmin (fibrinolysin) in hemostasis disorders reported in most patients with hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening condition related to a severe systemic inflammatory state. Most patients with HLH had a partial ADAMTS-13 deficiency, and plasmin could induce a truncation of the C-terminal part of ADAMTS-13 and thus an open conformation. Objectives: To understand the effect of plasmin on ADAMTS-13, our study aimed to investigate ADAMTS-13 conformation in patients with HLH. Methods: Forty-five critically ill patients with HLH were prospectively enrolled between April 2015 and December 2018. ADAMTS-13 activity was measured by fluorescent resonance energy transfer-VWF73 assay, ADAMTS-13 antigen, and conformation with our homemade 3H9-enzyme-linked immunosorbent assay and 1C4-enzyme-linked immunosorbent assay. Results: ADAMTS-13 activity ranged from <10 to 65 IU/dL, and 41 of the 45 patients had a quantitative deficiency in ADAMTS-13 (activity <50 IU/dL). Twenty patients had a severe ADAMTS-13 deficiency (activity <20 IU/dL). ADAMTS-13 conformation was folded in all patients under normal conditions. Surprisingly, the switch of ADAMTS-13 conformation expected with the monoclonal antibody 17G2 (anti-CUB1) was disturbed in 6 patients (activity <20 IU/dL). Conclusion: Our study reported that ADAMTS-13 conformation is closed in HLH and provides an indirect proof that plasmin is not able to massively degrade ADAMTS-13. Further studies on glycosylation and citrullination profiles of ADAMTS-13 are needed to understand their role in HLH.
Language	English
Publishing date	2023-12-07
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1016/j.rpth.2023.102292
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Article ; Online: Improvement of recombinant ADAMTS13 production through a more optimal signal peptide or an N-terminal fusion protein.

Kangro, Kadri / Roose, Elien / Dekimpe, Charlotte / Vandenbulcke, Aline / Graça, Nuno A G / Voorberg, Jan / Ustav, Mart / Männik, Andres / Vanhoorelbeke, Karen

Journal of thrombosis and haemostasis : JTH

2022 Volume 20, Issue 10, Page(s) 2379–2385

Abstract: Background: Recombinant human ADAMTS13 (rADAMTS13) is a key protein in fundamental research for investigating its mode of action and the pathophysiology of thrombotic thrombocytopenic purpura (TTP). However, the expression of rADAMTS13 is quite low in ... ...

Abstract	Background: Recombinant human ADAMTS13 (rADAMTS13) is a key protein in fundamental research for investigating its mode of action and the pathophysiology of thrombotic thrombocytopenic purpura (TTP). However, the expression of rADAMTS13 is quite low in mammalian cells, which makes the production of the protein time-consuming and labor-intensive. Objectives: We aimed at increasing the yield of rADAMTS13 by (1) using a more optimal signal peptide (SP) and (2) constructing an N-terminal fusion protein of ADAMTS13 with human serum albumin domain 1 (AD1-ADAMTS13). Methods: Six SPs were investigated to select the most optimal SP. Expression plasmids containing the most optimal SP and ADAMTS13 cDNA or the fusion construct AD1-ADAMTS13 were generated and transiently transfected into CHOEBNALT85 cell-line. Expression levels of rADAMTS13 in expression medium were analyzed and compared with the expression level of rADAMTS13 with native SP (nat-SP). Results: Expression of rADAMTS13 with coagulation factor VII (FVII) SP was 3-fold higher (16.00 μg/ml) compared with the expression with nat-SP (5.03 μg/ml). The highest yields were obtained with AD1-ADAMTS13 protein with a 15-fold higher concentration (78.22 μg/ml) compared with the expression with nat-SP. The rADAMTS13 expressed with FVII-SP retained its activity (104.0%) to cleave von Willebrand factor, whereas AD1-ADAMTS13 demonstrated even higher activity (144.3%). Conclusion: We succeeded in generating expression vectors that yield (1) rADAMTS13 at higher levels because of more optimal FVII-SP and (2) high levels of AD1-ADAMTS13 N-terminal fusion protein. The highest expression levels were obtained with AD1-ADAMTS13 N-terminal fusion protein, which is paving the way for highly efficient protein production.
MeSH term(s)	ADAM Proteins/genetics ; ADAM Proteins/metabolism ; ADAMTS13 Protein/genetics ; ADAMTS13 Protein/metabolism ; Animals ; DNA, Complementary ; Factor VII/metabolism ; Humans ; Mammals/genetics ; Mammals/metabolism ; Protein Sorting Signals/genetics ; Purpura, Thrombotic Thrombocytopenic ; Recombinant Proteins/metabolism ; Serum Albumin, Human ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
Chemical Substances	DNA, Complementary ; Protein Sorting Signals ; Recombinant Proteins ; von Willebrand Factor ; Factor VII (9001-25-6) ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87) ; Serum Albumin, Human (ZIF514RVZR)
Language	English
Publishing date	2022-07-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.15819
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Article ; Online: Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity.

Tellier, Edwige / Widemann, Agnès / Cauchois, Raphaël / Faccini, Julien / Lagarde, Marie / Brun, Marion / Robert, Philippe / Robert, Stéphane / Bachelier, Richard / Poullin, Pascale / Roose, Elien / Vanhoorelbeke, Karen / Coppo, Paul / Dignat-George, Françoise / Kaplanski, Gilles

Haematologica

2023 Volume 108, Issue 4, Page(s) 1127–1140

Abstract: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) ... ...

Abstract	Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as a trigger of the disease has been suggested in animal models but remains to be demonstrated in humans. We prospectively obtained plasma from the first plasma exchange of 25 patients during iTTP acute phase. iTTP but not control plasma, induced a rapid VWF release and P-selectin exposure on the surface of dermal human micro-vascular endothelial cell (HMVEC-d), associated with angiopoietin-2 and endothelin-1 secretion, consistent with Weibel-Palade bodies exocytosis. Calcium (Ca2+) blockade significantly decreased VWF release, whereas iTTP plasma induced a rapid and sustained Ca2+ flux in HMVEC-d which correlated in retrospect, with disease severity and survival in 62 iTTP patients. F(ab)'2 fragments purified from the immunoglobulin G fraction of iTTP plasma mainly induced endothelial cell activation with additional minor roles for circulating free heme and nucleosomes, but not for complement. Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patients' B cells, but not serum from hereditary TTP, induced endothelial Ca2+ flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small intering RNA, significantly decreased the stimulating effects of iTTP immunoglobulin G. In conclusion, Ca2+-mediated endothelial cell activation constitutes a "second hit" of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target.
MeSH term(s)	Animals ; Humans ; Purpura, Thrombotic Thrombocytopenic ; Calcium ; von Willebrand Factor/metabolism ; Immunoglobulin G ; ADAMTS13 Protein ; Patient Acuity
Chemical Substances	Calcium (SY7Q814VUP) ; von Willebrand Factor ; Immunoglobulin G ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2023-04-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.280651
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Article ; Online: Generation and validation of small ADAMTS13 fragments for epitope mapping of anti-ADAMTS13 autoantibodies in immune-mediated thrombotic thrombocytopenic purpura.

Kangro, Kadri / Roose, Elien / Schelpe, An-Sofie / Tellier, Edwige / Kaplanski, Gilles / Voorberg, Jan / De Meyer, Simon F / Männik, Andres / Vanhoorelbeke, Karen

Research and practice in thrombosis and haemostasis

2020 Volume 4, Issue 5, Page(s) 918–930

Abstract: Background: In immune-mediated thrombotic thrombocytopenic purpura (iTTP), patients develop an immune response against the multidomain enzyme ADAMTS13. ADAMTS13 consists of a metalloprotease (M) and disintegrin-like (D) domain, 8 thrombospondin type 1 ... ...

Abstract	Background: In immune-mediated thrombotic thrombocytopenic purpura (iTTP), patients develop an immune response against the multidomain enzyme ADAMTS13. ADAMTS13 consists of a metalloprotease (M) and disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). Previous epitope mapping studies have used relatively large overlapping ADAMTS13 fragments. Objectives: We aimed at developing small nonoverlapping ADAMTS13 fragments to fine map anti-ADAMTS13 autoantibodies in iTTP patients. Methods: A library of 16 ADAMTS13 fragments, comprising several small (M, DT, C, S, T2-T5, T6-T8, CUB1, CUB2), and some larger fragments with overlapping domains (MDT, MDTC, DTC, CS, T2-T8, CUB1-2, MDTCS, T2-C2), were generated. All fragments, and ADAMTS13, were expressed as a fusion protein with albumin domain 1, and purified. The folding of the fragments was tested using 17 anti-ADAMTS13 monoclonal antibodies with known epitopes. An epitope mapping assay using small ADAMTS13 fragments was set up, and validated by analyzing 18 iTTP patient samples. Results: Validation with the monoclonal antibodies demonstrated that single S and CUB1 were not correctly folded, and therefore CS and CUB1-2 fragments were selected instead of single C, S, CUB1, and CUB2 fragments. Epitope mapping of antibodies of patients with iTTP confirmed that 6 nonoverlapping ADAMTS13 fragments M, DT, CS, T2-T5, T6-T8, and CUB1-2 were sufficient to accurately determine the antibody-binding sites. Conclusion: We have developed a tool to profile patients with iTTP according to their anti-ADAMTS13 antibodies for a better insight in their immune response.
Language	English
Publishing date	2020-06-25
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1002/rth2.12379
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Article ; Online: Antibodies that conformationally activate ADAMTS13 allosterically enhance metalloprotease domain function.

Schelpe, An-Sofie / Petri, Anastasis / Roose, Elien / Pareyn, Inge / Deckmyn, Hans / De Meyer, Simon F / Crawley, James T B / Vanhoorelbeke, Karen

Blood advances

2020 Volume 4, Issue 6, Page(s) 1072–1080

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. ... ...

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.
MeSH term(s)	ADAMTS13 Protein ; Animals ; Catalytic Domain ; Metalloproteases ; Mice ; Protein Binding ; Proteolysis ; von Willebrand Factor/metabolism
Chemical Substances	von Willebrand Factor ; Metalloproteases (EC 3.4.-) ; ADAMTS13 protein, mouse (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2020-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2019001375
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In stock of ZB MED Cologne/Königswinter

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

Full text online

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito