Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice.
We have determined the crystal structure of I-Ag7, an integral component in murine type I diabetes development. Several features distinguish I-Ag7 from other non-autoimmune-associated MHC class II molecules, including novel peptide and heterodimer pairing interactions. The binding groove of I-Ag7 is unusual at both terminal ends, with a potentially solvent-exposed channel at the base of the P1 pocket and a widened entrance to the P9 pocket. Peptide binding studies with variants of the hen egg lysozyme I-Ag7 epitope HEL(11-25) support a comprehensive structure-based I-Ag7 binding motif. Residues critical for T cell recognition were investigated with a panel of HEL(11-25)-restricted clones, which uncovered P1 anchor-dependent structural variations. These results establish a framework for future experiments directed at understanding the role of I-Ag7 in autoimmunity.
Latek
R R
RR
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Suri
A
A
Petzold
S J
SJ
Nelson
C A
CA
Kanagawa
O
O
Unanue
E R
ER
Fremont
D H
DH
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D002645:Chickens; D018360:Crystallography, X-Ray; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D019281:Dimerization; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009113:Muramidase / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D010455:Peptides; D009113:Muramidase