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Crystal Structure of the Major Diabetes Autoantigen Insulinoma-Associated Protein 2 Reveals Distinctive Immune Epitopes

From the Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea

Address correspondence and reprint requests to Seong Eon Ryu, PhD, or Seung Jun Kim, PhD, Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Euh-eun-dong, Yuseong-gu, Daejeon 305-333, Korea. E-mail: ryuse{at}kribb.re.kr or ksj{at}kribb.re.kr

Key Words: IA-2, insulinoma-associated protein 2 • IA-2p, PTP-like domain of IA-2 • LAR, leukocyte antigen-related • MHC, major histocompatibility complex • PTEN, phosphatase and tensin homolog deleted on chromosome 10 • PTP, protein tyrosine phosphatase • RPTP, receptor PTP

Insulinoma-associated protein-2 (IA-2) is a major autoantigen in type 1 diabetes that occurs through autoimmune-mediated ß-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 ß-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.

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