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

DOI: 10.1016/j.celrep.2022.110959

Authors: Lucy C. Walters (University of Oxford) , Daniel Rozbesky (Charles University) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Max Quastel (University of Oxford) , Hong Sun (University of Oxford; The First Affiliated Hospital, China Medical University) , Sebastian Springer (Jacobs University Bremen) , Robert P. Rambo (Diamond Light Source) , Fiyaz Mohammed (University of Birmingham) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , Andrew J. Mcmichael (University of Oxford) , Geraldine M. Gillespie (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 39

State: Published (Approved)
Published: June 2022
Diamond Proposal Number(s): 19946

Abstract: 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.

Journal Keywords: MHC-E; HLA-E; small-angle X-ray scatter; SAXS; X-ray crystallography; VL9; MHC Ia; NK cells; NKG2A; CD8 T cells; T cell receptor

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 20/06/2022 09:08

Documents:
1-s2.0-S2211124722007410-main.pdf

Discipline Tags:

Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)