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

2022; Cell Press; Volume: 39; Issue: 11 Linguagem: Inglês

10.1016/j.celrep.2022.110959

2639-1856

Lucy C. Walters, Daniel Rozbeský, Karl Harlos, Max Quastel, Hong Sun, Sebastian Springer, Robert P. Rambo, Fiyaz Mohammed, E. Yvonne Jones, Andrew J. McMichael, Geraldine M. Gillespie,

Immunotherapy and Immune Responses

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.