NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes.
NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes.
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NKG2D 通过选择性机械调节配体构象变化来区分不同的配体
DOI：
10.15252/embj.2021107739
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发表时间：
2022-12-17
期刊：
影响因子：
--
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Fan J;Shi J;Zhang Y;Liu J;An C;Zhu H;Wu P;Hu W;Qin R;Yao D;Shou X;Xu Y;Tong Z;Wen X;Xu J;Zhang J;Fang W;Lou J;Yin W;Chen W
刺激性免疫受体NKG2D结合不同的配体，引发不同的抗肿瘤和抗病毒免疫应答。近二十年来，人们一直在考虑基于静态晶体结构和溶液中结合亲和力的两种相互冲突的简并识别模型。NKG2D是否以及如何识别和区分不同的配体仍不清楚。使用基于活细胞的单分子生物力学试验，我们表征了在不存在或存在机械力的情况下NKG2D与不同配体相互作用的原位结合动力学。我们发现，机械力的施加选择性地延长了NKG2D与配体云母和MICB的相互作用寿命，但与ULBP的相互作用寿命没有延长，并且力增强的结合对云母比对其他配体更明显。我们还整合了转向分子动力学模拟和诱变，以揭示力诱导的云母旋转构象变化，包括在其与NKG2D的结合界面上形成额外的氢键，从而阻碍云母在力作用下的解离。我们进一步提供了动力学触发模型，以揭示力依赖性亲和力决定NKG2D配体识别及其下游NK细胞活化。总之，我们的结果表明NKG2D具有识别不同配体的辨别能力，这取决于选择性机械力诱导的配体构象变化。力诱导的配体亲和力和构象改变允许免疫受体NKG2D识别不同的配体，并触发下游自然杀伤细胞活化的不同信号传导反应。
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. Force‐induced alterations of ligand affinity and conformation allow immune receptor NKG2D to recognize different ligands and trigger distinct signaling responses for downstream natural killer cell activation.
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在肿瘤浸润淋巴细胞上表达的孤儿T细胞受体的抗原鉴定。
影响因子：
64.5
作者：
Gee MH;Han A;Lofgren SM;Beausang JF;Mendoza JL;Birnbaum ME;Bethune MT;Fischer S;Yang X;Gomez-Eerland R;Bingham DB;Sibener LV;Fernandes RA;Velasco A;Baltimore D;Schumacher TN;Khatri P;Quake SR;Davis MM;Garcia KC
通讯作者：
Garcia KC
影响因子：
7.3
作者：
Bálint Š;Lopes FB;Davis DM
通讯作者：
Davis DM
影响因子：
3.4
作者：
Chesla, SE;Selvaraj, P;Zhu, C
通讯作者：
Zhu, C
DOI：
10.1073/pnas.88.14.6279
发表时间：
1991-07-01
影响因子：
11.1
作者：
EINSPAHR, KJ;ABRAHAM, RT;LEIBSON, PJ
通讯作者：
LEIBSON, PJ
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T