Selector function of MHC I molecules is determined by protein plasticity
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 <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.
1-15
Bailey, Alistair
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Dalchau, Neil
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Carter, Rachel
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Emmott, Stephen
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Phillips, Andrew
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Werner, Jorn M.
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Elliott, Tim
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20 October 2015
Bailey, Alistair
541e2cd9-ac72-4058-9293-def64fc2c284
Dalchau, Neil
41e37635-b4ee-483a-9bb9-867b2d453bc7
Carter, Rachel
8199d829-6dc4-4b09-b58e-a7757d40dacf
Emmott, Stephen
893d0078-6e8d-43e6-bead-4fabe90d135a
Phillips, Andrew
d379dc3d-fce9-422b-aaec-605eb732dcd7
Werner, Jorn M.
1b02513a-8310-4f4f-adac-dc2a466bd115
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
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].
(doi:10.1038/srep14928).
(PMID:26482009)
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 <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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srep14928.pdf
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Accepted/In Press date: 9 September 2015
e-pub ahead of print date: 20 October 2015
Published date: 20 October 2015
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 383203
URI: http://eprints.soton.ac.uk/id/eprint/383203
PURE UUID: 2767cc40-765e-4fac-8d34-c3462391abc5
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Date deposited: 12 Nov 2015 11:23
Last modified: 15 Mar 2024 03:47
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Contributors
Author:
Alistair Bailey
Author:
Neil Dalchau
Author:
Rachel Carter
Author:
Stephen Emmott
Author:
Andrew Phillips
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