4Z78

Weak TCR binding to an unstable insulin epitope drives type 1 diabetes

Summary for 4Z78

• Entry DOI: 10.2210/pdb4z78/pdb
• Descriptor: H-2 class I histocompatibility antigen, K-D alpha chain, Beta-2-microglobulin, Insulin, ... (7 entities in total)
• Functional Keywords: immunoglobulin, h-2kd, type 1 diabetes, immune system
• Biological source: Mus musculus (House Mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01902; Secreted : P61769 P01308
• Total number of polymer chains: 9
• Total formula weight: 137896.68

Authors

Rizkallah, P.J.,Cole, D.K. (deposition date: 2015-04-06, release date: 2015-06-24, Last modification date: 2024-10-16)

Primary citation

Motozono, C.,Pearson, J.A.,De Leenheer, E.,Rizkallah, P.J.,Beck, K.,Trimby, A.,Sewell, A.K.,Wong, F.S.,Cole, D.K.
Distortion of the Major Histocompatibility Complex Class I Binding Groove to Accommodate an Insulin-derived 10-Mer Peptide.
J.Biol.Chem., 290:18924-18933, 2015

PubMed 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.

PubMed: 26085090
DOI: 10.1074/jbc.M114.622522

Experimental method

X-RAY DIFFRACTION (2.304 Å)