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The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, K(b)-Y84C, in which two α-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound high-affinity peptide. K(b)-Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (β2m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and β2m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by β2m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that β2m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.

Original publication




Journal article


Journal of cell science

Publication Date





2885 - 2897


Molecular Life Science Center, Jacobs University Bremen, 28759 Bremen, Germany.


T-Lymphocytes, Hela Cells, 3T3 Cells, Animals, Mice, Inbred C57BL, Humans, Mice, Peptides, Histocompatibility Antigens Class I, H-2 Antigens, Epitopes, Lymphocyte Activation, Endocytosis, Antigen Presentation, Protein Structure, Secondary, Models, Molecular