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Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes

LC. Walters, D. Rozbesky, K. Harlos, M. Quastel, H. Sun, S. Springer, RP. Rambo, F. Mohammed, EY. Jones, AJ. McMichael, GM. Gillespie

. 2022 ; 39 (11) : 110959. [pub] 2022Jun14

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22018006

MHC-E regulates NK cells by displaying MHC class Ia signal peptides (VL9) to NKG2A:CD94 receptors. MHC-E can also present sequence-diverse, lower-affinity, pathogen-derived peptides to T cell receptors (TCRs) on CD8+ T cells. To understand these affinity differences, human MHC-E (HLA-E)-VL9 versus pathogen-derived peptide structures are compared. Small-angle X-ray scatter (SAXS) measures biophysical parameters in solution, allowing comparison with crystal structures. For HLA-E-VL9, there is concordance between SAXS and crystal parameters. In contrast, HLA-E-bound pathogen-derived peptides produce larger SAXS dimensions that reduce to their crystallographic dimensions only when excess peptide is supplied. Further crystallographic analysis demonstrates three amino acids, exclusive to MHC-E, that not only position VL9 close to the α2 helix, but also allow non-VL9 peptide binding with re-configuration of a key TCR-interacting α2 region. Thus, non-VL9-bound peptides introduce an alternative peptide-binding motif and surface recognition landscape, providing a likely basis for VL9- and non-VL9-HLA-E immune discrimination.

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$a MHC-E regulates NK cells by displaying MHC class Ia signal peptides (VL9) to NKG2A:CD94 receptors. MHC-E can also present sequence-diverse, lower-affinity, pathogen-derived peptides to T cell receptors (TCRs) on CD8+ T cells. To understand these affinity differences, human MHC-E (HLA-E)-VL9 versus pathogen-derived peptide structures are compared. Small-angle X-ray scatter (SAXS) measures biophysical parameters in solution, allowing comparison with crystal structures. For HLA-E-VL9, there is concordance between SAXS and crystal parameters. In contrast, HLA-E-bound pathogen-derived peptides produce larger SAXS dimensions that reduce to their crystallographic dimensions only when excess peptide is supplied. Further crystallographic analysis demonstrates three amino acids, exclusive to MHC-E, that not only position VL9 close to the α2 helix, but also allow non-VL9 peptide binding with re-configuration of a key TCR-interacting α2 region. Thus, non-VL9-bound peptides introduce an alternative peptide-binding motif and surface recognition landscape, providing a likely basis for VL9- and non-VL9-HLA-E immune discrimination.
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$a Rozbesky, Daniel $u Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
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$a Harlos, Karl $u Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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$a Quastel, Max $u Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK
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$a Sun, Hong $u Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK; Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China
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$a Springer, Sebastian $u Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany
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$a Rambo, Robert P $u Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, UK
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$a Mohammed, Fiyaz $u Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
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$a Jones, E Yvonne $u Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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$a McMichael, Andrew J $u Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK. Electronic address: andrew.mcmichael@ndm.ox.ac.uk
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$a Gillespie, Geraldine M $u Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK. Electronic address: geraldine.gillespie@ndm.ox.ac.uk
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