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

Journal article

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

Authors: Walters, LC; Rozbesky, D; Harlos, K; Quastel, M; Sun, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Reports
• Volume: 39
• Issue: 11
• Article number: 110959
• Publication date: 2022-06-14
• Acceptance date: 2022-05-23
• DOI: 10.1016/j.celrep.2022.110959
• ISSN: 2211-1247
• Pmid: 35705051
• Language: English
• Keywords: small angle; histocompatibility antigens class I; FFR; CD8-positive T-lymphocytes; NK cell lectin-like receptor subfamily C; X-ray diffraction; humans; scattering; protein binding; protein conformation; peptides