Selector function of MHC I molecules is determined by protein plasticity.
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.
Institute for Life Sciences, Building 85, University of Southampton, SO17 1BJ, UK.|Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.|Centre for Biological Sciences, Faculty of Natural &Environmental Sciences, Building 85, University of Southampton, SO17 1BJ, UK.
Alistair
A
Bailey
Computational Science Laboratory, Microsoft Research, 21 Station Road, Cambridge, CB1 2FB, UK.
Neil
N
Dalchau
Institute for Life Sciences, Building 85, University of Southampton, SO17 1BJ, UK.|Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
Rachel
R
Carter
Computational Science Laboratory, Microsoft Research, 21 Station Road, Cambridge, CB1 2FB, UK.
Stephen
S
Emmott
Computational Science Laboratory, Microsoft Research, 21 Station Road, Cambridge, CB1 2FB, UK.
Andrew
A
Phillips
Institute for Life Sciences, Building 85, University of Southampton, SO17 1BJ, UK.|Centre for Biological Sciences, Faculty of Natural &Environmental Sciences, Building 85, University of Southampton, SO17 1BJ, UK.
Jörn M
JM
Werner
Institute for Life Sciences, Building 85, University of Southampton, SO17 1BJ, UK.|Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
Tim
T
Elliott
D000483:Alleles; D017951:Antigen Presentation; D001665:Binding Sites; D059948:HLA-B44 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
D059948:HLA-B44 Antigen; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D010455:Peptides; C107762:tapasin