The Ministry of Education Key Laboratory of Protein Science, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing 100084, China.
The Ministry of Education Key Laboratory of Protein Science, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Structure. 2024 Oct 3;32(10):1640-1651.e5. doi: 10.1016/j.str.2024.07.010. Epub 2024 Aug 6.
Interleukin (IL)-12 is a heterodimeric pro-inflammatory cytokine. Our cryoelectron microscopy structure determination of human IL-12 in complex with IL-12Rβ1 and IL-12Rβ2 at a resolution of 3.75 Å reveals that IL-12Rβ2 primarily interacts with the IL-12p35 subunit via its N-terminal Ig-like domain, while IL-12Rβ1 binds to the p40 subunit with its N-terminal fibronectin III domain. This binding mode of IL-12 with its receptors is similar to that of IL-23 but shows notable differences with other cytokines. Through structural information and biochemical assays, we identified Y62, Y189, and K192 as key residues in IL-12p35, which bind to IL-12Rβ2 with high affinity and mediate IL-12 signal transduction. Furthermore, structural comparisons reveal two distinctive conformational states and structural plasticity of the heterodimeric interface in IL-12. As a result, our study advances our understanding of IL-12 signal initiation and opens up new opportunities for the engineering and therapeutic targeting of IL-12.
白细胞介素（IL）-12 是一种异二聚体促炎细胞因子。我们通过 3.75Å 的分辨率冷冻电镜结构测定，确定了人源 IL-12 与 IL-12Rβ1 和 IL-12Rβ2 复合物的结构，揭示了 IL-12Rβ2 主要通过其 N 端免疫球蛋白样结构域与 IL-12p35 亚基相互作用，而 IL-12Rβ1 则通过其 N 端纤维连接蛋白 III 结构域与 p40 亚基结合。这种 IL-12 与其受体的结合模式类似于 IL-23，但与其他细胞因子有明显的区别。通过结构信息和生化分析，我们确定了 IL-12p35 中的 Y62、Y189 和 K192 是与 IL-12Rβ2 高亲和力结合并介导 IL-12 信号转导的关键残基。此外，结构比较揭示了 IL-12 异二聚体界面的两种独特构象状态和结构可塑性。因此，我们的研究增进了对 IL-12 信号起始的理解，并为 IL-12 的工程改造和治疗靶向提供了新的机会。
