Evidence for invariant chain 85-101 (CLIP) binding in the antigen binding site of MHC class II molecules.
The region of invariant chain encompassing residues 81-104 is critical for association with MHC class II molecules. This segment of invariant chain, termed CLIP for Class II-associated invariant chain Peptides, has been shown to inhibit antigenic peptide binding and T cell stimulation. Polymorphism affects the ability of CLIP to inhibit antigenic peptide binding, suggesting that CLIP may occupy the MHC II antigen binding site directly. However, CLIP may also mediate inhibition by binding to an alternate site causing an allosteric change to prevent antigenic peptide binding. The relationship between the apparent dissociation constant in the presence of a competitor (Kapp) and the competitor concentration can be examined to determine the nature of competition between two ligands. In competitive binding experiments between CLIP and antigenic peptide we find a linear dependence of Kapp on competitor concentration. These data are consistent with CLIP and antigenic peptide competing for the same site on the MHC class II molecule, thus arguing against an allosteric mechanism of CLIP inhibition. Mildly acidic conditions are thought to promote peptide loading in the endosome compartment by facilitating CLIP dissociation and enhancing antigenic peptide association. We have compared the effect of acidic pH on the equilibrium binding of murine CLIP and antigenic peptide to MHC class II molecules. Like antigenic peptide, CLIP binding can be greatly enhanced at mildly acidic pH, suggesting that a passive competitive mechanism for CLIP removal may not be sufficient to achieve loading of antigenic peptide in the endosome.
Bangia
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Department of Immunology, University of Toronto, Ontario, Canada.
Watts
T H
TH
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D011992:Endosomes / Q000378:metabolism; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006825:Hybridomas / Q000276:immunology; D006863:Hydrogen-Ion Concentration; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D014407:Tumor Cells, Cultured
D000941:Antigens; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D010446:Peptide Fragments; C045084:invariant chain