title: Peptide-independent stabilization of MHC class I molecules breaches cellular quality control.
abstract: 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.
authors.affiliation: Molecular Life Science Center, Jacobs University Bremen, 28759 Bremen, Germany.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Hein
authors.affiliation: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Uchtenhagen
authors.affiliation: Molecular Life Science Center, Jacobs University Bremen, 28759 Bremen, Germany.
authors.forename: Esam Tolba
authors.initials: ET
authors.lastname: Abualrous
authors.affiliation: Molecular Life Science Center, Jacobs University Bremen, 28759 Bremen, Germany.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Saini
authors.affiliation: Molecular Life Science Center, Jacobs University Bremen, 28759 Bremen, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Janßen
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, Hampshire SO16 6YD, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Van Hateren
authors.affiliation: Department of Otorhinolaryngology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Wiek
authors.affiliation: Department of Otorhinolaryngology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: Division of Translational Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Momburg
authors.affiliation: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, Hampshire SO16 6YD, UK sebastian.springer@queens.oxon.org T.J.Elliott@soton.ac.uk.
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.affiliation: Molecular Life Science Center, Jacobs University Bremen, 28759 Bremen, Germany sebastian.springer@queens.oxon.org T.J.Elliott@soton.ac.uk.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Springer
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, Hampshire SO16 6YD, UK.
authors.forename: Denise
authors.initials: D
authors.lastname: Boulanger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017951:Antigen Presentation; D004705:Endocytosis; D000939:Epitopes; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000939:Epitopes; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides
keywords: Antigen presentation; ER quality control; Endocytosis; Major histocompatibility complex