Selector function of MHC I molecules is determined by protein plasticity

• Main Authors: Bailey, Alistair (Author), Dalchau, Neil (Author), Carter, Rachel (Author), Emmott, Stephen (Author), Phillips, Andrew (Author), Werner, Jorn M. (Author), Elliott, Tim (Author)
• Format: Article
• Language: English
• Published: 2015-10-20.
• Subjects: Article
• Online Access: Get fulltext

 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 <em>in vivo</em> 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 <em>in vivo</em> 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 {\alpha}₃ domain of MHC I allosterically, resulting in enhanced peptide selector function.