Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 31, Pages 18924-18933Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.622522
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Funding
- Wellcome Trust ISSF grant
- United Kingdom Biotechnology and Biological Sciences Research Council [BB/H001085/1]
- Medical Research Council [G0901155]
- Diabetes UK PhD studentship
- Research Councils United Kingdom fellowship
- BBSRC [BB/H001085/1] Funding Source: UKRI
- MRC [G0901155] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H001085/1] Funding Source: researchfish
- Medical Research Council [G0901155] Funding Source: researchfish
- Wellcome Trust [100327/Z/12/Z] Funding Source: researchfish
- Wellcome Trust [100327/Z/12/Z] Funding Source: Wellcome Trust
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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 beta-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.
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