Selector function of MHC I molecules is determined by protein plasticity

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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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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1038/srep14928
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RB Pathology
Organisations: Cancer Sciences
ePrint ID: 383203
Date :
Date Event
9 September 2015Accepted/In Press
20 October 2015Published
Date Deposited: 12 Nov 2015 11:23
Last Modified: 17 Apr 2017 04:56
Further Information:Google Scholar

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