3WS3

Crystal Structure of H-2D in complex with an insulin derived peptide

Summary for 3WS3

• Entry DOI: 10.2210/pdb3ws3/pdb
• Related: 3WS6
• Descriptor: H-2 class I histocompatibility antigen, D-B alpha chain, Beta-2-microglobulin, Insulin derived 9-mer peptide, ... (4 entities in total)
• Functional Keywords: class i mhc, major histocompatibility complex, insulin, h-2d, structural genomics, psi-biology, new york structural genomics research consortium, nysgrc, immune system
• Biological source: Mus musculus (mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01899; Secreted: P01887
• Total number of polymer chains: 6
• Total formula weight: 89484.39

Authors

Kumar, P.R.,Mukherjee, G.,Samanta, D.,DiLorenzo, T.P.,Almo, S.C.,Immune Function Network,New York Structural Genomics Research Consortium (NYSGRC) (deposition date: 2014-02-28, release date: 2014-03-26, Last modification date: 2024-11-13)

Primary citation

Lamont, D.,Mukherjee, G.,Kumar, P.R.,Samanta, D.,McPhee, C.G.,Kay, T.W.H.,Almo, S.C.,DiLorenzo, T.P.,Serreze, D.V.
Compensatory mechanisms allow undersized anchor-deficient class I MHC ligands to mediate pathogenic autoreactive T cell responses
J. Immunol., 193:2135-2146, 2014

PubMed Abstract: Self-reactive T cells must escape thymic negative selection to mediate pathogenic autoimmunity. In the NOD mouse model of autoimmune diabetes, several β cell-cytotoxic CD8 T cell populations are known, with the most aggressive of these represented by AI4, a T cell clone with promiscuous Ag-recognition characteristics. We identified a long-elusive β cell-specific ligand for AI4 as an unusually short H-2D(b)-binding 7-mer peptide lacking a C-terminal anchor residue and derived from the insulin A chain (InsA14-20). Crystallography reveals that compensatory mechanisms permit peptides lacking a C-terminal anchor to bind sufficiently to the MHC to enable destructive T cell responses, yet allow cognate T cells to avoid negative selection. InsA14-20 shares two solvent-exposed residues with previously identified AI4 ligands, providing a structural explanation for AI4's promiscuity. Detection of AI4-like T cells, using mimotopes of InsA14-20 with improved H-2D(b)-binding characteristics, establishes the AI4-like T cell population as a consistent feature of the islet infiltrates of NOD mice. Our work establishes undersized peptides as previously unrecognized targets of autoreactive CD8 T cells and presents a strategy for their further exploration as Ags in autoimmune disease.

PubMed: 25063871
DOI: 10.4049/jimmunol.1400997

Experimental method

X-RAY DIFFRACTION (2.335 Å)