title: The first step of peptide selection in antigen presentation by MHC class I molecules.
abstract: MHC class I molecules present a variable but limited repertoire of antigenic peptides for T-cell recognition. Understanding how peptide selection is achieved requires mechanistic insights into the interactions between the MHC I and candidate peptides. We find that, at first encounter, MHC I H-2K(b) considers a wide range of peptides, including those with expanded N termini and unfitting anchor residues. Discrimination occurs in the second step, when noncanonical peptides dissociate with faster exchange rates. This second step exhibits remarkable temperature sensitivity, as illustrated by numerous noncanonical peptides presented by H-2K(b) in cells cultured at 26 °C relative to 37 °C. Crystallographic analyses of H-2K(b)-peptide complexes suggest that a conformational adaptation of H-2K(b) drives the decisive step in peptide selection. We propose that MHC class I molecules consider initially a large peptide pool, subsequently refined by a temperature-sensitive induced-fit mechanism to retain the canonical peptide repertoire.
authors.affiliation: Departments of Cell Biology and.
authors.forename: Malgorzata A
authors.initials: MA
authors.lastname: Garstka
authors.affiliation: Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fish
authors.affiliation: Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Patrick H N
authors.initials: PH
authors.lastname: Celie
authors.affiliation: Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Robbie P
authors.initials: RP
authors.lastname: Joosten
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: George M C
authors.initials: GM
authors.lastname: Janssen
authors.affiliation: Departments of Cell Biology and.
authors.forename: Ilana
authors.initials: I
authors.lastname: Berlin
authors.affiliation: Departments of Cell Biology and.
authors.forename: Rieuwert
authors.initials: R
authors.lastname: Hoppes
authors.affiliation: Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Magda
authors.initials: M
authors.lastname: Stadnik
authors.affiliation: Departments of Cell Biology and.
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.affiliation: Departments of Cell Biology and.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and.
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.affiliation: Departments of Cell Biology and j.neefjes@nki.nl.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019277:Entropy; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D007700:Kinetics; D010455:Peptides / Q000737:chemistry* / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides
keywords: anchor residues; antigen presentation; dynamics; entropy; peptide binding