title: Molecular mechanism of peptide editing in the tapasin-MHC I complex.
abstract: Immune recognition of infected or malignantly transformed cells relies on antigenic peptides exposed at the cell surface by major histocompatibility complex class I (MHC I) molecules. Selection and loading of peptides onto MHC I is orchestrated by the peptide-loading complex (PLC), a multiprotein assembly whose structure has not yet been resolved. Tapasin, a central component of the PLC, stabilises MHC I and catalyses the exchange of low-affinity against high-affinity, immunodominant peptides. Up to now, the molecular basis of this peptide editing mechanism remained elusive. Here, using all-atom molecular dynamics (MD) simulations, we unravel the atomic details of how tapasin and antigen peptides act on the MHC I binding groove. Force distribution analysis reveals an intriguing molecular tug-of-war mechanism: only high-affinity peptides can exert sufficiently large forces to close the binding groove, thus overcoming the opposite forces exerted by tapasin to open it. Tapasin therefore accelerates the release of low-affinity peptides until a high-affinity antigen binds, promoting subsequent PLC break-down. Fluctuation and entropy analyses show how tapasin chaperones MHC I by stabilising it in a peptide-receptive conformation. Our results explain previous experiments and mark a key step towards a better understanding of adaptive immunity.
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780, Germany.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fisette
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wingbermühle
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, 60438, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
authors.affiliation: Lehrstuhl für Theoretische Chemie, Ruhr-University Bochum, 44780, Germany.
authors.forename: Lars V
authors.initials: LV
authors.lastname: Schäfer
mesh_terms: D055162:Biocatalysis; D019277:Entropy; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains
chemical_list: D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones; D010455:Peptides; C107762:tapasin