Structure of the murine CD94–NKG2A receptor in complex with Qa-1b presenting an MHC-I leader peptide

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.

© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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