Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA.
Nat Commun. 2024 Nov 12;15(1):9776. doi: 10.1038/s41467-024-54124-1.
Oncostatin M (OSM) is a unique Interleukin 6 (IL-6) family cytokine that plays pivotal roles in numerous biological events by signaling via two types of receptor complexes. While type I OSM receptor complex is formed by glycoprotein 130 (gp130) heterodimerization with Leukemia Inhibitory Factor receptor (LIFR), type II OSM receptor complex is composed of gp130 and OSM receptor (OSMR). OSM is an important contributor to multiple inflammatory diseases and cancers while OSM inhibition has been shown to be effective at reducing symptoms, making OSM an attractive therapeutic target. Using cryogenic electron microscopy (cryo-EM), we characterize full extracellular assemblies of human type I OSM receptor complex and mouse type II OSM receptor complex. The juxtamembrane domains of both complexes are situated in close proximity due to acute bends of the receptors. The rigid N-terminal extension of OSM contributes to gp130 binding and OSM signaling. Neither glycosylation nor pro-domain cleavage of OSM affects its activity. Mutagenesis identifies multiple OSM and OSMR residues crucial for complex formation and signaling. Our data reveal the structural basis for the assemblies of both type I and type II OSM receptor complexes and provide insights for modulation of OSM signaling in therapeutics.
抑瘤素 M（OSM）是一种独特的白细胞介素 6（IL-6）家族细胞因子，通过两种类型的受体复合物信号转导，在许多生物学事件中发挥关键作用。I 型 OSM 受体复合物由糖蛋白 130（gp130）与白血病抑制因子受体（LIFR）的异二聚化形成，而 II 型 OSM 受体复合物由 gp130 和 OSM 受体（OSMR）组成。OSM 是多种炎症性疾病和癌症的重要贡献者，而 OSM 抑制已被证明能有效减轻症状，使 OSM 成为有吸引力的治疗靶点。我们使用低温电子显微镜（cryo-EM）对人 I 型 OSM 受体复合物和鼠 II 型 OSM 受体复合物的全长细胞外组装体进行了表征。由于受体的急性弯曲，两种复合物的跨膜区都位于非常接近的位置。OSM 的刚性 N 端延伸有助于 gp130 的结合和 OSM 信号转导。OSM 的糖基化或前导序列切割都不会影响其活性。突变分析确定了多个 OSM 和 OSMR 残基对于复合物形成和信号转导至关重要。我们的数据揭示了两种 OSM 受体复合物组装的结构基础，并为治疗中 OSM 信号转导的调节提供了见解。
