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 ORCID: https://orcid.org/0000-0002-2020-7522 and Vivian, Julian P. 2024. Structure of the murine CD94–NKG2A receptor in complex with Qa-1b presenting an MHC-I leader peptide. The FEBS Journal 291 (7) , pp. 1530-1544. 10.1111/febs.17050

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc/4.0/
Publisher:	Wiley
ISSN:	1742-464X
Funders:	NHMRC, Victorian Cancer Agency Fellowship
Date of First Compliant Deposit:	11 January 2024
Date of Acceptance:	27 December 2023
Last Modified:	20 May 2024 11:32
URI:	https://orca.cardiff.ac.uk/id/eprint/165416

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