title: Distortion of the Major Histocompatibility Complex Class I Binding Groove to Accommodate an Insulin-derived 10-Mer Peptide.
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.
authors.affiliation: From the Division of Infection and Immunity and the Department of Immunology, Kinki University School of Medicine, Osaka 589-8511, Japan, and.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Motozono
authors.affiliation: the Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Pearson
authors.affiliation: the Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Evy
authors.initials: E
authors.lastname: De Leenheer
authors.affiliation: From the Division of Infection and Immunity and.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.affiliation: the Cardiff University School of Dentistry, Heath Park, Cardiff CF14 4XY, United Kingdom.
authors.forename: Konrad
authors.initials: K
authors.lastname: Beck
authors.affiliation: From the Division of Infection and Immunity and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Trimby
authors.affiliation: From the Division of Infection and Immunity and.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.affiliation: the Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom, wongfs@cf.ac.uk.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: From the Division of Infection and Immunity and coledk@cf.ac.uk.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000378:metabolism; D007328:Insulin / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs
chemical_list: D015395:Histocompatibility Antigens Class I; D007328:Insulin; D010446:Peptide Fragments
keywords: NOD mouse; T-cell receptor (TCR); beta cell; insulin; pMHC; type 1 diabetes; x-ray crystallography