Abstract
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.
Highlights
Insulinoma-associated protein-2 (IA-2) is a major autoantigen in type 1 diabetes that occurs through autoimmunemediated -cell destruction
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
The crystal structure of IA-2p was determined by molecular replacement and refined to 2.1-Å resolutions (Table 1)
Summary
In the crystal structure of IA-2p, Asn858 and Trp799 are located on the opposite side of Glu836, indicating that the three residues cannot form a binding surface (Fig. 4). Structural display of residues implicated in the autoantibody interactions reveals two major epitope regions in IA-2p: one in the WPAE loop region and the other in the lower part of the central -sheet region (Fig. 5). The residues implicated as the epitope of 2_sera (Asn862 and Val859) and antibody 96/3 (Tyr855, Asn838, and Glu836) are located in the same region, constituting the second cluster of the B-cell epitope. Clustering of residues implicated in two independent studies indicates that the surface comprised of Asn862, Val859, and Glu836 is likely an antigenic hot spot, and this hot spot may be extended to include Tyr855 and Asn838 (Fig. 5). When the IA-2 protein is proteolytically cleaved into linear peptides for presentation on MHC molecules, the tertiary structure of IA-2 is disrupted, and the B-cell epitope residues are able to form very different antigenic structures for recognition by T-cell receptors
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