6WYT

Crystal structure of anti-Muscle Specific Kinase (MuSK) Fab, MuSK1B

6WYT の概要

• エントリーDOI: 10.2210/pdb6wyt/pdb
• 分子名称: MuSK1B heavy chain, MuSK1B light chain, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: human fab, anti-musk, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46646.68

構造登録者

Vieni, C.,Ekiert, D. (登録日: 2020-05-13, 公開日: 2020-07-29, 最終更新日: 2024-10-30)

主引用文献

Fichtner, M.L.,Vieni, C.,Redler, R.L.,Kolich, L.,Jiang, R.,Takata, K.,Stathopoulos, P.,Suarez, P.A.,Nowak, R.J.,Burden, S.J.,Ekiert, D.C.,O'Connor, K.C.
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis.
J.Exp.Med., 217:-, 2020

PubMed Abstract: Pathogenic muscle-specific tyrosine kinase (MuSK)-specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm-exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.

PubMed: 32820331
DOI: 10.1084/jem.20200513

実験手法

X-RAY DIFFRACTION (1.75 Å)