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The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity, and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and α3 domain of MHC I allosterically, resulting in enhanced peptide selector function.

Original publication

DOI

10.1038/srep14928

Type

Journal article

Journal

Scientific reports

Publication Date

20/10/2015

Volume

5

Addresses

Institute for Life Sciences, Building 85, University of Southampton, SO17 1BJ, UK.

Keywords

Humans, Peptides, Membrane Transport Proteins, Histocompatibility Antigens Class I, Antigen Presentation, Binding Sites, Protein Conformation, Protein Binding, Alleles, Models, Molecular, HLA-B44 Antigen