Distortion of the major histocompatibility complex class I binding groove to accommodate an insulin-derived 10-Mer peptide

Motozono, Chihiro, Pearson, James A. ORCID: https://orcid.org/0000-0002-2867-2269, De Leenheer, Evy, Rizkallah, Pierre J. ORCID: https://orcid.org/0000-0002-9290-0369, Beck, Konrad ORCID: https://orcid.org/0000-0001-5098-9484, Trimby, Andrew, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396 2015. Distortion of the major histocompatibility complex class I binding groove to accommodate an insulin-derived 10-Mer peptide. Journal of Biological Chemistry 290 (31) , pp. 18924-18933. 10.1074/jbc.M114.622522

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Additional Information:	This is an open access article under the CC-BY license.
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Funders:	Wellcome
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	17 June 2015
Last Modified:	05 Jan 2024 08:15
URI:	https://orca.cardiff.ac.uk/id/eprint/75686

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