1. Crystal structure of the major diabetes autoantigen insulinoma-associated protein 2 reveals distinctive immune epitopes
- Author
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Dae Gwin Jeong, Seong Eon Ryu, Seung Jun Kim, Sook Kyung Jeong, and Tae-Seong Yoon
- Subjects
Models, Molecular ,Protein Conformation ,Endocrinology, Diabetes and Metabolism ,Ubiquitin-Protein Ligases ,Protein domain ,Molecular Sequence Data ,Protein tyrosine phosphatase ,medicine.disease_cause ,Crystallography, X-Ray ,Autoantigens ,Epitope ,Autoimmunity ,Inhibitor of Apoptosis Proteins ,Immune system ,Protein structure ,Internal Medicine ,medicine ,Humans ,Receptor-Like Protein Tyrosine Phosphatases, Class 8 ,Amino Acid Sequence ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,biology ,Mutagenesis ,Active site ,Membrane Proteins ,Baculoviral IAP Repeat-Containing 3 Protein ,Cell biology ,Kinetics ,Diabetes Mellitus, Type 1 ,Immunology ,biology.protein ,Protein Tyrosine Phosphatases - Abstract
Insulinoma-associated protein-2 (IA-2) is a major autoantigen in type 1 diabetes that occurs through autoimmune-mediated β-cell destruction. We present here the crystal structure of the protein tyrosine phosphatase (PTP)-like domain of human IA-2. The structure reveals a canonical PTP domain with the closed WPD loop over the active site pocket, explaining the lack of enzyme activity in the native protein. The structural interpretation of previous mutagenesis studies indicates that the B-cell epitopes are concentrated on two distinctive regions on peripheral loops of the central β-sheet surrounding T-cell epitopes within the sheet. The detailed structural information on immune epitopes provides a framework for the future development of immune intervention strategies against diabetes.
- Published
- 2006