The MHC class II molecule I-Ag7 exists in alternate conformations that are peptide dependent.
Insulin-dependent diabetes mellitus is an autoimmune disease that is genetically linked to the HLA class II molecule DQ in humans and to MHC I-Ag7 in nonobese diabetic mice. The I-Ag7 beta-chain is unique and contains multiple polymorphisms, at least one of which is shared with DQ alleles linked to insulin-dependent diabetes mellitus. This polymorphism occurs at position 57 in the beta-chain, in which aspartic acid is mutated to a serine, a change that results in the loss of an interchain salt bridge between alphaArg76 and betaAsp57 at the periphery of the peptide binding groove. Using mAbs we have identified alternative conformations of I-Ag7 class II molecules. By using an invariant chain construct with various peptides engineered into the class II-associated invariant chain peptide (CLIP) region we have found that formation of these conformations is dependent on the peptide occupying the binding groove. Blocking studies with these Abs indicate that these conformations are present at the cell surface and are capable of interactions with TCRs that result in T cell activation.
Department of Pathology, Committee on Immunology and Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
L S
LS
Arneson
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M
Peterson
A J
AJ
Sant
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017951:Antigen Presentation / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C045084:invariant chain