Structure and assembly of the human IL-12 signaling complex

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2024-08-06 DOI:10.1016/j.str.2024.07.010

引用次数: 0

Abstract

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.

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人类 IL-12 信号复合体的结构与组装

白细胞介素（IL）-12 是一种异二聚体促炎细胞因子。我们以 3.75 Å 的分辨率测定了人 IL-12 与 IL-12Rβ1 和 IL-12Rβ2 复合物的冷冻电镜结构，结果显示 IL-12Rβ2 主要通过其 N 端 Ig 样结构域与 IL-12p35 亚基相互作用，而 IL-12Rβ1 则通过其 N 端纤维蛋白 III 结构域与 p40 亚基结合。IL-12 与其受体的这种结合模式与 IL-23 相似，但与其他细胞因子有明显不同。通过结构信息和生化试验，我们发现 Y62、Y189 和 K192 是 IL-12p35 中的关键残基，它们与 IL-12Rβ2 结合的亲和力很高，并介导 IL-12 信号转导。此外，结构比较揭示了 IL-12 中异源二聚体界面的两种不同构象状态和结构可塑性。因此，我们的研究推进了我们对 IL-12 信号启动的理解，并为 IL-12 的工程和治疗靶向开辟了新的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.