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Sci Rep. 2015 Oct 20;5:14928. doi: 10.1038/srep14928.

Selector function of MHC I molecules is determined by protein plasticity.

Author information

1
Institute for Life Sciences, Building 85, University of Southampton, SO17 1BJ, UK.
2
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
3
Centre for Biological Sciences, Faculty of Natural &Environmental Sciences, Building 85, University of Southampton, SO17 1BJ, UK.
4
Computational Science Laboratory, Microsoft Research, 21 Station Road, Cambridge, CB1 2FB, UK.

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.

PMID:
26482009
PMCID:
PMC5224517
DOI:
10.1038/srep14928
[Indexed for MEDLINE]
Free PMC Article

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