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Structure of the murine CD94–NKG2A receptor in complex with Qa-1b presenting an MHC-I leader peptide
MacLachlan, Bruce J. Sullivan, Lucy C. Brooks, Andrew G. Rossjohn, Jamie Vivian, Julian P.
MacLachlan, Bruce J.
Sullivan, Lucy C.
Brooks, Andrew G.
Rossjohn, Jamie
Vivian, Julian P.
Abstract
The heterodimeric natural killer cells antigen CD94 (CD94)–NKG2-A/NKG2-B type II integral membrane protein (NKG2A) receptor family expressed on human and mouse natural killer (NK) cells monitors global major histocompatibility complex (MHC) class I cell surface expression levels through binding to MHC class Ia-derived leader sequence peptides presented by HLA class I histocompatibility antigen, alpha chain E (HLA-E; in humans) or H-2 class I histocompatibility antigen, D-37 (Qa-1b; in mice). Although the molecular basis underpinning human CD94–NKG2A recognition of HLA-E is known, the equivalent interaction in the murine setting is not. By determining the high-resolution crystal structure of murine CD94–NKG2A in complex with Qa-1b presenting the Qa-1 determinant modifier peptide (QDM), we resolved the mode of binding. Compared to the human homologue, the murine CD94–NKG2A–Qa-1b–QDM displayed alterations in the distribution of interactions across CD94 and NKG2A subunits that coincide with differences in electrostatic complementarity of the ternary complex and the lack of cross-species reactivity. Nevertheless, we show that Qa-1b could be modified through W65R + N73I mutations to mimic HLA-E, facilitating binding with both human and murine CD94–NKG2A. These data underscore human and murine CD94–NKG2A cross-species heterogeneity and provide a foundation for humanising Qa-1b in immune system models.
Keywords
immune checkpoint molecules, immune system, inhibitory membrane receptors, MHC-class I, natural killer cell education
Date
2024
Type
Journal article
Journal
The FEBS Journal
Book
Volume
291
Issue
7
Page Range
1530-1544
Article Number
ACU Department
Marketing and Communications
Research Office
Research Office
Collections
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY-NC 4.0
File Access
Open
Notes
© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.