Structural insights into the interaction of IL-33 with its receptors
Structural insights into the interaction of IL-33 with its receptors
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DOI：
10.1073/pnas.1308651110
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发表时间：
2013-09-10
影响因子：
11.1
通讯作者：
Wang, Xinquan
中科院分区：
文献类型：
--
作者：
Liu, Xi;Hammel, Michal;Wang, Xinquan
白细胞介素（IL）-33是IL-1家族的重要成员，其在宿主防御和疾病的先天性和适应性免疫应答中具有多效性活性。它通过其配体结合主要受体ST 2和IL-1受体辅助蛋白（IL-1 RAcP）发出信号，两者都是IL-1受体家族的成员。为了阐明IL-33与其受体的相互作用，我们以3.27埃的分辨率测定了IL-33与ST 2胞外域复合物的晶体结构。结合基于结构的诱变和结合试验，结构结果定义了ST 2特异性识别IL-33的分子机制。与IL-1家族中的其他配体-受体复合物的结构比较表明，表面电荷互补性在确定IL-1初级受体的配体结合特异性中是至关重要的。结合晶体学和小角X射线散射研究表明，ST 2具有铰链之间的D3域和D1 D2模块的灵活性，而IL-1 RAcP在溶液中的未结合状态下表现出刚性构象。ST 2的分子柔性提供了对IL-1初级受体在配体结合后的结构域水平构象变化的结构见解，并且IL-1 RAcP的刚性解释了其不能直接结合配体。来自小角X射线散射分析的IL-33-ST 2-IL-1 RAcP复合物的溶液结构类似于IL-1 β-IL-1 RI-IL-1 RAcP和IL-1 β-IL-1 RI-IL-1 RAcP晶体结构。集体的结果赋予IL-33的结构-功能关系，支持和扩展IL-1家族中的配体-受体组装和激活的一般模型。
Interleukin (IL)-33 is an important member of the IL-1 family that has pleiotropic activities in innate and adaptive immune responses in host defense and disease. It signals through its ligand-binding primary receptor ST2 and IL-1 receptor accessory protein (IL-1RAcP), both of which are members of the IL-1 receptor family. To clarify the interaction of IL-33 with its receptors, we determined the crystal structure of IL-33 in complex with the ectodomain of ST2 at a resolution of 3.27 angstrom. Coupled with structure-based mutagenesis and binding assay, the structural results define the molecular mechanism by which ST2 specifically recognizes IL-33. Structural comparison with other ligand-receptor complexes in the IL-1 family indicates that surface-charge complementarity is critical in determining ligand-binding specificity of IL-1 primary receptors. Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. The molecular flexibility of ST2 provides structural insights into domain-level conformational change of IL-1 primary receptors upon ligand binding, and the rigidity of IL-1RAcP explains its inability to bind ligands directly. The solution architecture of IL-33-ST2-IL-1RAcP complex from small-angle X-ray-scattering analysis resembles IL-1 beta-IL-1RII-IL-1RAcP and IL-1 beta-IL-1RI-IL-1RAcP crystal structures. The collective results confer IL-33 structure-function relationships, supporting and extending a general model for ligand-receptor assembly and activation in the IL-1 family.