title: Mechanistic Basis for Epitope Proofreading in the Peptide-Loading Complex.
abstract: The peptide-loading complex plays a pivotal role in Ag processing and is thus central to the efficient immune recognition of virally and malignantly transformed cells. The underlying mechanism by which MHC class I (MHC I) molecules sample immunodominant peptide epitopes, however, remains poorly understood. In this article, we delineate the interaction between tapasin (Tsn) and MHC I molecules. We followed the process of peptide editing in real time after ultra-fast photoconversion to pseudoempty MHC I molecules. Tsn discriminates between MHC I loaded with optimal and MHC I bound to suboptimal cargo. This differential interaction is key to understanding the kinetics of epitope proofreading. To elucidate the underlying mechanism at the atomic level, we modeled the Tsn/MHC I complex using all-atom molecular dynamics simulations. We present a catalytic working cycle, in which Tsn binds to MHC I with suboptimal cargo and thereby adjusts the energy landscape in favor of MHC I complexes with immunodominant epitopes.
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany;
authors.forename: Gerda
authors.initials: G
authors.lastname: Fleischmann
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780 Bochum, Germany; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fisette
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany;
authors.forename: Ralph
authors.initials: R
authors.lastname: Wieneke
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany;
authors.forename: Franz
authors.initials: F
authors.lastname: Tumulka
authors.affiliation: Molecular Life Science, Jacobs University Bremen, 28759 Bremen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Schneeweiss
authors.affiliation: Molecular Life Science, Jacobs University Bremen, 28759 Bremen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Springer
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780 Bochum, Germany; and.
authors.forename: Lars V
authors.initials: LV
authors.lastname: Schäfer
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, 60438 Frankfurt, Germany; tampe@em.uni-frankfurt.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
mesh_terms: D000595:Amino Acid Sequence; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005454:Fluorescence Polarization; D059948:HLA-B44 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000939:Epitopes; D059948:HLA-B44 Antigen; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D026901:Membrane Transport Proteins; D010455:Peptides; C107762:tapasin; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human