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Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins

Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins
Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins
Major histocompatibility complex class I molecules (MHC I) present peptides to cytotoxic T-cells at the surface of almost all nucleated cells. The function of MHC I molecules is to select high affinity peptides from a large intracellular pool and they are assisted in this process by co-factor molecules, notably tapasin. In contrast to mammals, MHC homozygous chickens express a single MHC I gene locus, termed BF2, which is hypothesised to have co-evolved with the highly polymorphic tapasin within stable haplotypes. The BF2 molecules of the B15 and B19 haplotypes have recently been shown to differ in their interactions with tapasin and in their peptide selection properties. This study investigated whether these observations might be explained by differences in the protein plasticity that is encoded into the MHC I structure by primary sequence polymorphisms. Furthermore, we aimed to demonstrate the utility of a complimentary modelling approach to the understanding of complex experimental data. Combining mechanistic molecular dynamics simulations and the primary sequence based technique of statistical coupling analysis, we show how two of the eight polymorphisms between BF2*15:01 and BF2*19:01 facilitate differences in plasticity. We show that BF2*15:01 is intrinsically more plastic than BF2*19:01, exploring more conformations in the absence of peptide. We identify a protein sector of contiguous residues connecting the membrane bound ?3 domain and the heavy chain peptide binding site. This sector contains two of the eight polymorphic residues. One is residue 22 in the peptide binding domain and the other 220 is in the ?3 domain, a putative tapasin binding site. These observations are in correspondence with the experimentally observed functional differences of these molecules and suggest a mechanism for how modulation of MHC I plasticity by tapasin catalyses peptide selection allosterically.
1932-6203
e89657-[11pp]
Bailey, Alistair
541e2cd9-ac72-4058-9293-def64fc2c284
van Hateren, Andy
e345fa3c-d89c-4b91-947e-c1d818cc7f71
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Werner, Jörn M.
1b02513a-8310-4f4f-adac-dc2a466bd115
Wang, Junwen
d1276de8-2d94-4a69-b72d-21d52f00e59f
Wang, Junwen
d1276de8-2d94-4a69-b72d-21d52f00e59f
Bailey, Alistair
541e2cd9-ac72-4058-9293-def64fc2c284
van Hateren, Andy
e345fa3c-d89c-4b91-947e-c1d818cc7f71
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Werner, Jörn M.
1b02513a-8310-4f4f-adac-dc2a466bd115

Bailey, Alistair, van Hateren, Andy, Elliott, Tim and Werner, Jörn M., Wang, Junwen(ed.) (2014) Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins PLoS ONE, 9, (2), e89657-[11pp]. (doi:10.1371/journal.pone.0089657). (PMID:24586943).

Record type: Article

Abstract

Major histocompatibility complex class I molecules (MHC I) present peptides to cytotoxic T-cells at the surface of almost all nucleated cells. The function of MHC I molecules is to select high affinity peptides from a large intracellular pool and they are assisted in this process by co-factor molecules, notably tapasin. In contrast to mammals, MHC homozygous chickens express a single MHC I gene locus, termed BF2, which is hypothesised to have co-evolved with the highly polymorphic tapasin within stable haplotypes. The BF2 molecules of the B15 and B19 haplotypes have recently been shown to differ in their interactions with tapasin and in their peptide selection properties. This study investigated whether these observations might be explained by differences in the protein plasticity that is encoded into the MHC I structure by primary sequence polymorphisms. Furthermore, we aimed to demonstrate the utility of a complimentary modelling approach to the understanding of complex experimental data. Combining mechanistic molecular dynamics simulations and the primary sequence based technique of statistical coupling analysis, we show how two of the eight polymorphisms between BF2*15:01 and BF2*19:01 facilitate differences in plasticity. We show that BF2*15:01 is intrinsically more plastic than BF2*19:01, exploring more conformations in the absence of peptide. We identify a protein sector of contiguous residues connecting the membrane bound ?3 domain and the heavy chain peptide binding site. This sector contains two of the eight polymorphic residues. One is residue 22 in the peptide binding domain and the other 220 is in the ?3 domain, a putative tapasin binding site. These observations are in correspondence with the experimentally observed functional differences of these molecules and suggest a mechanism for how modulation of MHC I plasticity by tapasin catalyses peptide selection allosterically.

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Accepted/In Press date: 21 January 2014
Published date: 20 February 2014
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 368153
URI: http://eprints.soton.ac.uk/id/eprint/368153
ISSN: 1932-6203
PURE UUID: c332e70a-7140-4c17-8764-f8b8c86420fe
ORCID for Alistair Bailey: ORCID iD orcid.org/0000-0003-0023-8679
ORCID for Tim Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Jörn M. Werner: ORCID iD orcid.org/0000-0002-4712-1833

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Date deposited: 19 Aug 2014 10:18
Last modified: 18 Jul 2017 01:50

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Contributors

Editor: Junwen Wang
Author: Alistair Bailey ORCID iD
Author: Andy van Hateren
Author: Tim Elliott ORCID iD
Author: Jörn M. Werner ORCID iD

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