دورية أكاديمية
N-glycan-mediated shielding of ADAMTS13 prevents binding of pathogenic autoantibodies in immune-mediated TTP.
| العنوان: | N-glycan-mediated shielding of ADAMTS13 prevents binding of pathogenic autoantibodies in immune-mediated TTP. |
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| المؤلفون: | Ercig B; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands.; PharmaTarget BV, Maastricht, The Netherlands.; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Graça NAG; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands.; Icosagen Cell Factory OÜ, Kambja vald, Tartumaa, Estonia., Kangro K; Icosagen Cell Factory OÜ, Kambja vald, Tartumaa, Estonia.; Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium., Arfman T; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., Wichapong K; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Hrdinová J; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands.; PharmaTarget BV, Maastricht, The Netherlands.; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Kaijen P; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., van Alphen FPJ; Research Facilities, Sanquin, Amsterdam, The Netherlands., van den Biggelaar M; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands., Vanhoorelbeke K; Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium., Veyradier A; Service d'Hématologie Biologique and EA3518-Institut Universitaire d'Hématologie, Groupe Hospitalier Saint Louis-Lariboisière, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Diderot, Paris, France.; Centre de Référence des Microangiopathies Thrombotiques and., Coppo P; Centre de Référence des Microangiopathies Thrombotiques and.; Service d'Hématologie, Hôpital Saint-Antoine, AP-HP, Paris, France.; Sorbonne Université, UPMC Université Paris, Paris, France; and., Reutelingsperger C; PharmaTarget BV, Maastricht, The Netherlands.; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Nicolaes GAF; PharmaTarget BV, Maastricht, The Netherlands.; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Männik A; Icosagen Cell Factory OÜ, Kambja vald, Tartumaa, Estonia., Voorberg J; Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands.; Department of Experimental Vascular Medicine, Amsterdam UMC, Amsterdam, The Netherlands. |
| المصدر: | Blood [Blood] 2021 May 13; Vol. 137 (19), pp. 2694-2698. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Video-Audio Media |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Antigen-Antibody Reactions*, ADAMTS13 Protein/*immunology , Antigen-Antibody Complex/*chemistry , Autoantibodies/*immunology , Autoantigens/*immunology , Polysaccharides/*immunology , Purpura, Thrombotic Thrombocytopenic/*immunology, ADAMTS13 Protein/chemistry ; ADAMTS13 Protein/metabolism ; Amino Acid Substitution ; Amino Acids ; Antibodies, Monoclonal/immunology ; Antigen-Antibody Complex/immunology ; Autoantibodies/metabolism ; Autoantigens/chemistry ; Autoantigens/metabolism ; Epitopes/immunology ; Epitopes/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Domains ; von Willebrand Factor/metabolism |
| مستخلص: | Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disorder caused by the development of autoantibodies targeting different domains of ADAMTS13. Profiling studies have shown that residues R568, F592, R660, Y661, and Y665 within exosite-3 of the spacer domain provide an immunodominant region of ADAMTS13 for pathogenic autoantibodies that develop in patients with iTTP. Modification of these 5 core residues with the goal of reducing autoantibody binding revealed a significant tradeoff between autoantibody resistance and proteolytic activity. Here, we employed structural bioinformatics to identify a larger epitope landscape on the ADAMTS13 spacer domain. Models of spacer-antibody complexes predicted that residues R568, L591, F592, K608, M609, R636, L637, R639, R660, Y661, Y665, and L668 contribute to an expanded epitope within the spacer domain. Based on bioinformatics-guided predictions, we designed a panel of N-glycan insertions in this expanded epitope to reduce the binding of spacer domain autoantibodies. One N-glycan variant (NGLY3-ADAMTS13, containing a K608N substitution) showed strongly reduced reactivity with TTP patient sera (28%) as compared with WT-ADAMTS13 (100%). Insertion of an N-glycan at amino acid position 608 did not interfere with processing of von Willebrand factor, positioning the resulting NGLY3-ADAMTS13 variant as a potential novel therapeutic option for treatment of iTTP. (© 2021 by The American Society of Hematology.) |
| التعليقات: | Comment in: Blood. 2021 May 13;137(19):2575-2576. (PMID: 33983424) |
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| المشرفين على المادة: | 0 (Amino Acids) 0 (Antibodies, Monoclonal) 0 (Antigen-Antibody Complex) 0 (Autoantibodies) 0 (Autoantigens) 0 (Epitopes) 0 (Polysaccharides) 0 (von Willebrand Factor) EC 3.4.24.87 (ADAMTS13 Protein) EC 3.4.24.87 (ADAMTS13 protein, human) |
| تواريخ الأحداث: | Date Created: 20210205 Date Completed: 20211206 Latest Revision: 20221108 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9635527 |
| DOI: | 10.1182/blood.2020007972 |
| PMID: | 33544829 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2020007972 |