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Selector function of MHC I molecules is determined by protein plasticity

Record type: Article

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}<sub>3</sub> domain of MHC I allosterically, resulting in enhanced peptide selector function.

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Bailey, Alistair, Dalchau, Neil, Carter, Rachel, Emmott, Stephen, Phillips, Andrew, Werner, Jorn M. and Elliott, Tim (2015) Selector function of MHC I molecules is determined by protein plasticity Scientific Reports, 5, (14928), pp. 1-15. (doi:10.1038/srep14928). (PMID:26482009).

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Accepted/In Press date: 9 September 2015
Published date: 20 October 2015
Organisations: Cancer Sciences


Local EPrints ID: 383203
PURE UUID: 2767cc40-765e-4fac-8d34-c3462391abc5
ORCID for Alistair Bailey: ORCID iD
ORCID for Jorn M. Werner: ORCID iD
ORCID for Tim Elliott: ORCID iD

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Date deposited: 12 Nov 2015 11:23
Last modified: 17 Jul 2017 20:14

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Author: Alistair Bailey ORCID iD
Author: Neil Dalchau
Author: Rachel Carter
Author: Stephen Emmott
Author: Andrew Phillips
Author: Jorn M. Werner ORCID iD
Author: Tim Elliott ORCID iD

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