8BXR

Titin FnIII-domain I109-I111 (I/A4-A/A6) from the MIR region

8BXR の概要

• エントリーDOI: 10.2210/pdb8bxr/pdb
• 分子名称: Titin, 1,2-ETHANEDIOL (3 entities in total)
• 機能のキーワード: titin, mir, i-band, i/a junction, fniii, structural protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33683.09

構造登録者

Mayans, O.,Fleming, J.R.,Williams, R. (登録日: 2022-12-09, 公開日: 2023-02-15, 最終更新日: 2024-06-19)

主引用文献

Stergiou, C.,Williams, R.,Fleming, J.R.,Zouvelou, V.,Ninou, E.,Andreetta, F.,Rinaldi, E.,Simoncini, O.,Mantegazza, R.,Bogomolovas, J.,Tzartos, J.,Labeit, S.,Mayans, O.,Tzartos, S.
Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis.
Biomedicines, 11:-, 2023

PubMed Abstract: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.

PubMed: 36830985
DOI: 10.3390/biomedicines11020449

実験手法

X-RAY DIFFRACTION (2.7 Å)