NKG2D discriminates diverse ligands through selectively mechano‐regulated ligand conformational changes
Abstract: Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti‐tumor and anti‐virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in‐solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands still remain unclear. Using live‐cell‐based single‐molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force‐strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force‐induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force‐dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force‐induced ligand conformational changes.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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NKG2D discriminates diverse ligands through selectively mechano‐regulated ligand conformational changes ; day:16 ; month:12 ; year:2021 ; extent:28
The EMBO journal / European Molecular Biology Organization ; (16.12.2021) (gesamt 28)
- Creator
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Fan, Juan
Shi, Jiawei
Zhang, Yong
Liu, Junwei
An, Chenyi
Zhu, Huaying
Wu, Peng
Hu, Wei
Qin, Rui
Yao, Danmei
Shou, Xin
Xu, Yibing
Tong, Zhou
Wen, Xue
Xu, Jianpo
Zhang, Jin
Fang, Weijia
Lou, Jizhong
Yin, Weiwei
Chen, Wei
- DOI
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10.15252/embj.2021107739
- URN
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urn:nbn:de:101:1-2021121714010543695649
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:38 AM CEST
Data provider
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Associated
- Fan, Juan
- Shi, Jiawei
- Zhang, Yong
- Liu, Junwei
- An, Chenyi
- Zhu, Huaying
- Wu, Peng
- Hu, Wei
- Qin, Rui
- Yao, Danmei
- Shou, Xin
- Xu, Yibing
- Tong, Zhou
- Wen, Xue
- Xu, Jianpo
- Zhang, Jin
- Fang, Weijia
- Lou, Jizhong
- Yin, Weiwei
- Chen, Wei