Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes
Lucy C. Walters,
Daniel Rozbesky,
Karl Harlos,
Max Quastel,
Hong Sun,
Sebastian Springer,
Robert P. Rambo,
Fiyaz Mohammed,
E. Yvonne Jones,
Andrew J. McMichael,
Geraldine M. Gillespie
Affiliations
Lucy C. Walters
Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK
Daniel Rozbesky
Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
Karl Harlos
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Max Quastel
Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK
Hong Sun
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
Sebastian Springer
Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany
Robert P. Rambo
Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, UK
Fiyaz Mohammed
Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
E. Yvonne Jones
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
Andrew J. McMichael
Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK; Corresponding author
Geraldine M. Gillespie
Nuffield Department of Medicine Research Building, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK; Corresponding author
Summary: 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.
