Structure and interactions of the human programmed cell death 1 receptor.
Structure and interactions of the human programmed cell death 1 receptor.
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DOI：
10.1074/jbc.m112.448126
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发表时间：
2013-04-26
期刊：
影响因子：
--
通讯作者：
Davis SJ
中科院分区：
文献类型：
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作者：
Cheng X;Veverka V;Radhakrishnan A;Waters LC;Muskett FW;Morgan SH;Huo J;Yu C;Evans EJ;Leslie AJ;Griffiths M;Stubberfield C;Griffin R;Henry AJ;Jansson A;Ladbury JE;Ikemizu S;Carr MD;Davis SJ
背景：抑制性白细胞受体PD-1结合两种配体PD-L1和PD-L2。结果如下：核磁共振分析和严格的结合和热力学测量揭示了PD-1的结构和配体识别模式。结论：PD-L1和PD-L2与PD-1的结合不同，并且比预期的弱得多。意义：强抑制性信号传导可由弱相互作用受体启动。PD-1是一种由T细胞、B细胞和单核细胞表达的受体，是免疫应答的有效调节剂和有前景的治疗靶点。然而，人PD-1的结构和相互作用的特征并不完全。我们提出了基于核磁共振（NMR）的人PD-1胞外区的结构，并详细分析了其与配体PD-L1和PD-L2的相互作用。PD-1具有典型的免疫球蛋白超家族拓扑结构，但在GFCC′折叠的边缘不同，其是柔性的并且完全缺乏C″链。由配体结合诱导的PD-1骨架NMR信号的变化表明，尽管结合集中在GFCC′片层上，但PD-1与其两个配体的结合方式不同，并且小鼠PD-1·配体复合物的晶体结构不能完全解释。使用表面等离子体共振测量的这些相互作用的亲和力以及PD-L1与共刺激蛋白B7-1的亲和力显著弱于预期。PD-L2对人PD-1的亲和力比PD-L1高3-4倍，主要是由于PD-L2结合的解离速率低3倍。等温滴定量热法显示PD-1/PD-L1相互作用是熵驱动的，而PD-1/PD-L2结合具有大的熵分量。基于生物物理数据和定量表达数据的数学模拟表明，在活化的T细胞与抗原呈递细胞的相互作用期间，PD-L2对PD-1连接的贡献出乎意料地有限。这些发现为解释PD-1的重要功能提供了严格的结构和生物物理框架，并揭示了弱相互作用受体可以启动有效的抑制信号传导。
Background: The inhibitory leukocyte receptor PD-1 binds two ligands, PD-L1 and PD-L2. Results: Nuclear magnetic resonance analysis and rigorous binding and thermodynamic measurements reveal the structure of, and the mode of ligand recognition by, PD-1. Conclusion: PD-L1 and PD-L2 bind differently to PD-1 and much more weakly than expected. Significance: Potent inhibitory signaling can be initiated by weakly interacting receptors. PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC′ sheet, which is flexible and completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC′ sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1·ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3–4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.