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Eugster, A.* ; Kraus, G.* ; Lidzba, V.* ; Müller, D.* ; Jolink, M. ; Ziegler, A.-G. ; Bonifacio, E.

Cytoplasmic ends of tetraspanin 7 harbour epitopes recognised by autoantibodies in type 1 diabetes.

Diabetologia 62, 805-810 (2019)
Postprint DOI PMC
Open Access Green
Aims/hypothesis The beta cell protein tetraspanin 7 is a target of autoantibodies in individuals with type 1 diabetes. The aim of this study was to identify autoantibody epitope-containing regions and key residues for autoantibody binding.Methods Autoantibody epitope regions were identified by immunoprecipitation of luciferase-tagged single or multiple tetraspanin 7 domains using tetraspanin 7 antibody-positive sera. Subsequently, amino acids (AAs) relevant for autoantibody binding were identified by single AA mutations.Results In tetraspanin 7 antibody-positive sera, antibody binding was most frequent to tetraspanin 7 proteins that contained the NH2-terminal cytoplasmic domain 1 (C1; up to 39%) or COOH-terminal C3 (up to 22%). Binding to C3 was more frequent when the domain was expressed along with the flanking transmembrane domain, suggesting that conformation is likely to be important. Binding to external domains was not observed. Single AA mutations of C3 identified residues Y246, E247 and R239 as critical for COOH-terminal binding of 9/10, 10/10 and 8/10 sera tested, respectively. Mutation of cysteines adjacent to the transmembrane domain at either residues C235 or C236 resulted in both decreased (8/178 and 15/178 individuals, respectively; >twofold decrease) and increased (30/178 and 13/178 individuals, respectively; >twofold increase) binding in participant sera vs wild-type protein.Conclusions/interpretation We hypothesise that conformation and, potentially, modification of protein terminal ends of tetraspanin 7 may be important for autoantibody binding in type 1 diabetes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Autoantibodies ; Epitopes ; Glima 38 ; Tetraspanin 7 ; Type 1 Diabetes Mellitus
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Zeitschrift Diabetologia
Quellenangaben Band: 62, Heft: 5, Seiten: 805-810 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Berlin ; Heidelberg [u.a.]
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)
Institute of Diabetes Research Type 1 (IDF)