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Distortion of the Major Histocompatibility Complex Class I Binding Groove to Accommodate an Insulin-derived 10-Mer

Chihiro Motozono1, James A Pearson2, Evy De Leenheer2

  • 1From the Division of Infection and Immunity and the Department of Immunology, Kinki University School of Medicine, Osaka 589-8511, Japan, and.

The Journal of Biological Chemistry
|June 19, 2015
PubMed

The non-obese diabetic mouse model of type 1 diabetes continues to be an important tool for delineating the role of T-cell-mediated destruction of pancreatic β-cells. However, little is known about the molecular mechanisms that enable this disease pathway. We show that insulin reactivity by a CD8(+) T-cell clone, known to induce type 1 diabetes, is characterized by weak T-cell antigen receptor binding to a relatively unstable peptide-MHC. The structure of the native 9- and 10-mer insulin epitopes demonstrated that peptide residues 7 and 8 form a prominent solvent-exposed bulge that could potentially be the main focus of T-cell receptor binding. The C terminus of the peptide governed peptide-MHC stability. Unexpectedly, we further demonstrate a novel mode of flexible peptide presentation in which the MHC peptide-binding groove is able to "open the back door" to accommodate extra C-terminal peptide residues.

Keywords:
NOD mouseT-cell receptor (TCR)beta cellinsulinpMHCtype 1 diabetesx-ray crystallography

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