@article{bailey2015selector,
author = {Bailey, Alistair and Dalchau, Neil and Carter, Rachel and Emmott, Stephen and Phillips, Andrew and Werner, Jörn M. and Elliott, Tim},
title = {Selector function of MHC I molecules is determined by protein plasticity},
year = {2015},
month = {October},
abstract = {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.},
publisher = {Nature Publishing Group},
url = {http://approjects.co.za/?big=en-us/research/publication/selector-function-of-mhc-i-molecules-is-determined-by-protein-plasticity/},
pages = {14928},
journal = {Scientific Reports},
volume = {5},
edition = {Scientific Reports},
}