title: Plasticity of empty major histocompatibility complex class I molecules determines peptide-selector function.
abstract: Major histocompatibility complex class I (MHC I) proteins provide protection from intracellular pathogens and cancer via each of a cell's MHC I molecules binding and presenting a peptide to cytotoxic T lymphocytes. MHC I genes are highly polymorphic and can have significant diversity, with polymorphisms predominantly localised in the peptide-binding groove where they can change peptide-binding specificity. However, polymorphic residues may also determine other functional properties, such as how dependent MHC I alleles are on the peptide-loading complex for optimal acquisition of peptide cargo. We describe how differences in the peptide-binding properties of two MHC I alleles correlates with altered conformational flexibility in the peptide-empty state. We hypothesise that plasticity is an intrinsic property encoded by the protein sequence, and that co-ordinated movements of the membrane-proximal and membrane-distal domains collectively determines how dependent MHC I are on the peptide-loading complex for efficient assembly with high affinity peptides.
authors.affiliation: Institute for Life Sciences, Building 85, M55, University of Southampton, SO17 1BJ, UK; Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO16 6YD, UK. Electronic address: avh@soton.ac.uk.
authors.forename: Andy
authors.initials: A
authors.lastname: van Hateren
authors.affiliation: Institute for Life Sciences, Building 85, M55, University of Southampton, SO17 1BJ, UK; Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO16 6YD, UK; Centre for Biological Sciences, Faculty of Natural & Environmental Sciences, Building 85, M55, University of Southampton, SO17 1BJ, UK. Electronic address: ab604@soton.ac.uk.
authors.forename: Alistair
authors.initials: A
authors.lastname: Bailey
authors.affiliation: Institute for Life Sciences, Building 85, M55, University of Southampton, SO17 1BJ, UK; Centre for Biological Sciences, Faculty of Natural & Environmental Sciences, Building 85, M55, University of Southampton, SO17 1BJ, UK. Electronic address: J.M.Werner@soton.ac.uk.
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Werner
authors.affiliation: Institute for Life Sciences, Building 85, M55, University of Southampton, SO17 1BJ, UK; Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO16 6YD, UK. Electronic address: T.J.Elliott@soton.ac.uk.
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
mesh_terms: D000483:Alleles; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D010455:Peptides; C107762:tapasin
keywords: MHC class I; Peptide editing; Peptide selection; Protein plasticity; Tapasin
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