Crystal structure of the major diabetes autoantigen insulinoma-associated protein 2 reveals distinctive immune epitopes.
Insulinoma-associated protein-2 (IA-2) is a major autoantigen in type 1 diabetes that occurs through autoimmune-mediated beta-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 beta-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.
Kim
Seung Jun
SJ
Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Euh-eun-dong, Yuseong-gu, Daejeon 305-333, Korea.
Jeong
Dae Gwin
DG
Jeong
Sook Kyung
SK
Yoon
Tae-Seong
TS
Ryu
Seong Eon
SE
D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry* / Q000235:genetics*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018360:Crystallography, X-Ray; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D044767:Ubiquitin-Protein Ligases
D001324:Autoantigens; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8