<br>鼠 CD94–NKG2A 受体与呈递 MHC-I 前导肽的 Qa-1b 复合物的结构,The FEBS Journal

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鼠 CD94–NKG2A 受体与呈递 MHC-I 前导肽的 Qa-1b 复合物的结构
The FEBS Journal ( IF 5.5 ) Pub Date : 2023-12-29 , DOI: 10.1111/febs.17050
Bruce J MacLachlan ₁ , Lucy C Sullivan ₂ , Andrew G Brooks ₂ , Jamie Rossjohn _{1,

3} , Julian P Vivian ₁

Affiliation

人类和小鼠自然杀伤 (NK) 细胞上表达的异二聚自然杀伤细胞抗原 CD94 (CD94)–NKG2-A/NKG2-B II 型整合膜蛋白 (NKG2A) 受体家族监测全球主要组织相容性复合体 (MHC) I 类细胞通过与 HLA I 类组织相容性抗原、α 链 E（HLA-E；在人类中）或 H-2 I 类组织相容性抗原 D-37（Qa-1 ^b）呈递的 MHC Ia 类衍生前导序列肽结合，提高表面表达水平；在小鼠中）。尽管人类 CD94-NKG2A 识别 HLA-E 的分子基础已知，但小鼠环境中的等效相互作用尚不清楚。通过确定鼠 CD94–NKG2A 与呈递 Qa-1 决定簇修饰肽 (QDM) 的 Qa-1 ^b复合物的高分辨率晶体结构，我们解决了结合模式。与人类同源物相比，鼠 CD94–NKG2A–Qa-1 ^b –QDM 在 CD94 和 NKG2A 亚基之间的相互作用分布发生了变化，这与三元复合物的静电互补性差异和缺乏跨物种反应性相一致。尽管如此，我们表明 Qa-1b 可以通过 W65R + N73I 突变进行修饰以模拟 HLA-E，从而促进与人和鼠 CD94-NKG2A 的结合。这些数据强调了人类和小鼠 CD94-NKG2A 的跨物种异质性，并为免疫系统模型中 Qa-1b 人性化提供了基础。

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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-1^b; 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-1^b presenting the Qa-1 determinant modifier peptide (QDM), we resolved the mode of binding. Compared to the human homologue, the murine CD94–NKG2A–Qa-1^b–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.

更新日期：2023-12-29

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