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

DOI: 10.1074/jbc.M114.622522 DOI Help
PMID: 26085090 PMID Help

Authors: Chihiro Motozono (Cardiff University) , James A. Pearson (Cardiff University) , Evy De Leenheer (Cardiff University) , Pierre J. Rizkallah (Cardiff University) , Konrad Beck (Cardiff University) , Andrew Trimby (Cardiff University) , Andrew K. Sewell (Cardiff University) , F. Susan Wong (Cardiff University) , David K. Cole (Cardiff University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 290 (31) , PAGES 18924 - 18933

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 10462

Open Access Open Access

Abstract: 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.

Journal Keywords: Beta cell; insulin; T-cell receptor (TCR); type 1 diabetes; x-ray crystallography; NOD mouse; pMHC

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 12/10/2015 20:09

Documents:
Cole_JBC_July31_cover.pdf

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