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

Motozono, Chihiro, Pearson, James A., De Leenheer, Evy, Rizkallah, Pierre, Beck, Konrad, Trimby, Andrew R., Sewell, Andrew K., Wong, Florence Susan and Cole, David 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)
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: 12 Mar 2019 12:22
URI: http://orca.cf.ac.uk/id/eprint/75686

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