小柯机器人

美国斯坦福大学医学院K. Christopher Garcia小组揭示白细胞介素-17配体-受体轴的组织结构原则。这一研究成果于2022年7月21日在线发表在国际学术期刊《自然》上。

据介绍，白细胞介素-17（IL-17）家族的细胞因子和受体在宿主对感染的防御和炎症性疾病的发展中起着核心作用。功能性IL-17家族配体-受体信号组合的组成和结构仍不清楚。白细胞介素-17E（IL-17E或IL-25）是Th2免疫反应的关键调节因子，也是过敏性哮喘等炎症性疾病的驱动因素，需要IL-17受体A（IL-17RA）和IL-17RB来激发功能性反应。

研究人员使用冷冻电镜（cryo-EM）、单分子成像和基于细胞的信号传导方法相结合，研究了IL-25-IL-17RB二元和IL-25-IL-17RB-IL-17RA三元复合体。IL-25-IL-17RB-IL-17RA三元信号传导组件是一个c2对称的复合物，其中IL-25-IL-17RB同源二聚体通过"尖对尖"的几何形状被两个"翼状"的IL-17RA共受体包围，这是启动信号转导所需的关键受体-受体互动。IL-25仅与IL-17RB相互作用，以异构方式促进IL-17RB-IL-17RA尖对尖界面的形成。

由此产生的膜近端受体之间的巨大分离可能反映了细胞内结构域对信号传导的接近性限制。IL-17A-IL-17RA和IL-17A-IL-17RA-IL-17RC复合物的冷冻电镜结构显示，这种尖对尖的结构是IL-17受体家族的一个关键组织原则。此外，这些研究揭示了IL-17RA在IL-17细胞因子复合物中共享的双重作用，要么直接参与IL-17细胞因子，要么作为一个共同受体发挥作用。

附：英文原文

Title: Organizing Structural Principles of the Interleukin-17 Ligand-Receptor Axis

Author: Wilson, Steven C., Caveney, Nathanael A., Yen, Michelle, Pollmann, Christoph, Xiang, Xinyu, Jude, Kevin M., Hafer, Maximillian, Tsutsumi, Naotaka, Piehler, Jacob, Garcia, K. Christopher

Issue&Volume: 2022-07-21

Abstract: The interleukin-17 (IL-17) family of cytokines and receptors play central roles in host defense against infection, and development of inflammatory diseases1. The compositions and structures of functional IL-17 family ligand-receptor signaling assemblies remain unclear. Interleukin-17E (IL-17E or IL-25) is a key regulator of Th2 immune responses and driver of inflammatory diseases such as allergic asthma and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses2. Here, we studied IL-25–IL-17RB binary and IL-25–IL-17RB–IL-17RA ternary complexes using a combination of cryo-electron microscopy (cryo-EM), single-molecule imaging, and cell-based signaling approaches. The IL-25–IL-17RB–IL-17RA ternary signaling assembly is a c2-symmetric complex in which the IL-25–IL-17RB homodimer is flanked by two “wing-like” IL-17RA co-receptors through a “tip-to-tip” geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB–IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints by the intracellular domains for signaling. Cryo-EM structures of IL-17A–IL-17RA and IL-17A–IL-17RA–IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family, Furthermore, these studies reveal dual actions for IL-17RA sharing amongst IL-17 cytokine complexes, by either directly engaging IL-17 cytokines, or alternatively functioning as a co-receptor.

DOI: 10.1038/s41586-022-05116-y

Source: https://www.nature.com/articles/s41586-022-05116-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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