6WYR

Crystal structure of anti-Muscle Specific Kinase (MuSK) Fab, MuSK1A

Summary for 6WYR

• Entry DOI: 10.2210/pdb6wyr/pdb
• Descriptor: MuSK1A light chain, MuSK1A heavy chain, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: human fab, anti-musk, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 98214.66

Authors

Vieni, C.,Ekiert, D. (deposition date: 2020-05-13, release date: 2020-07-29, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)