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; Sebastien Springer; Robert P Rambo; Fiyaz Mohammed; E Yvonne Jones; Andrew J  McMichael; Geraldine M Gillespie

doi:10.1016/j.celrep.2022.110959

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, Sebastien Springer, Robert P Rambo, Fiyaz Mohammed, E Yvonne Jones, Andrew J McMichael^*, Geraldine M Gillespie^*

^*Corresponding author for this work

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

36 Downloads (Pure)

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.

Original language	English
Article number	110959
Number of pages	15
Journal	Cell Reports
Volume	39
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2022.110959
Publication status	Published - 14 Jun 2022

Bibliographical note

Acknowledgments:
This work was supported by grants from the BMGF (OPP1133649), MRC (MR/M019837/1), NIAID (5UM1AI126619-05 and 1UM1AI164567-01), and the Hester Cordelia Parsons Fund, Oxford University. D.R. was supported by the Czech Science Foundation (21-27204M) and Charles University (PRIMUS/21/SCI/003). We are grateful to Diamond Light Source for beamtime (proposal MX19946) and the staff of beamlines I03 and I04 for data collection assistance. We also thank Prof. Tao Dong and Dr. Yanchun Peng for provision of HLA-A∗02:01 heavy-chain material.

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

Access to Document

10.1016/j.celrep.2022.110959Licence: Creative Commons: Attribution (CC BY)

WaltersL2022PrimaryFinal published version, 5.5 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

@article{12422137ceb04a80a9be25853e8de517,

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

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.",

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",

author = "Walters, {Lucy C} and Daniel Rozbesky and Karl Harlos and Max Quastel and Hong Sun and Sebastien Springer and Rambo, {Robert P} and Fiyaz Mohammed and Jones, {E Yvonne} and McMichael, {Andrew J} and Gillespie, {Geraldine M}",

note = "Acknowledgments: This work was supported by grants from the BMGF (OPP1133649), MRC (MR/M019837/1), NIAID (5UM1AI126619-05 and 1UM1AI164567-01), and the Hester Cordelia Parsons Fund, Oxford University. D.R. was supported by the Czech Science Foundation (21-27204M) and Charles University (PRIMUS/21/SCI/003). We are grateful to Diamond Light Source for beamtime (proposal MX19946) and the staff of beamlines I03 and I04 for data collection assistance. We also thank Prof. Tao Dong and Dr. Yanchun Peng for provision of HLA-A∗02:01 heavy-chain material.",

year = "2022",

month = jun,

day = "14",

doi = "10.1016/j.celrep.2022.110959",

language = "English",

volume = "39",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "11",

}

TY - JOUR

T1 - Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes

AU - Walters, Lucy C

AU - Rozbesky, Daniel

AU - Harlos, Karl

AU - Quastel, Max

AU - Sun, Hong

AU - Springer, Sebastien

AU - Rambo, Robert P

AU - Mohammed, Fiyaz

AU - Jones, E Yvonne

AU - McMichael, Andrew J

AU - Gillespie, Geraldine M

N1 - Acknowledgments: This work was supported by grants from the BMGF (OPP1133649), MRC (MR/M019837/1), NIAID (5UM1AI126619-05 and 1UM1AI164567-01), and the Hester Cordelia Parsons Fund, Oxford University. D.R. was supported by the Czech Science Foundation (21-27204M) and Charles University (PRIMUS/21/SCI/003). We are grateful to Diamond Light Source for beamtime (proposal MX19946) and the staff of beamlines I03 and I04 for data collection assistance. We also thank Prof. Tao Dong and Dr. Yanchun Peng for provision of HLA-A∗02:01 heavy-chain material.

PY - 2022/6/14

Y1 - 2022/6/14

N2 - 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.

AB - 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.

KW - MHC-E

KW - HLA-E

KW - small-angle X-ray scatter

KW - SAXS

KW - X-ray crystallography

KW - VL9

KW - MHC Ia

KW - NK cells

KW - NKG2A

KW - CD8 T cells

KW - T cell receptor

U2 - 10.1016/j.celrep.2022.110959

DO - 10.1016/j.celrep.2022.110959

M3 - Article

SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 110959

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this