Detailed Structure of Mouse Interferon α2 and Its Interaction with Sortilin
Detailed Structure of Mouse Interferon α2 and Its Interaction with Sortilin
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小鼠干扰素α2的详细结构及其与分拣蛋白的相互作用
DOI：
10.1093/jb/mvab038
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发表时间：
2021
影响因子：
2.7
通讯作者：
Masaki Unno
中科院分区：
文献类型：
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作者：
Honoka Watanabe;Toshiki Yabe-Wada;Nobuyuki Onai;Masaki Unno
干扰素α（IFNα）是一种I型干扰素，是免疫系统对抗病毒的必需细胞因子。尽管已经报道了许多I型干扰素的结构，但大多数已知的IFNα结构都与其受体复合。游离IFNα的结构只有两个例子：一个是没有侧链信息的二聚体X射线结构;另一个是人IFNα的NMR结构。虽然我们已经证明分拣蛋白参与IFNα的分泌，但分子相互作用的细节和分泌机制仍不清楚。最近，我们解决了小鼠Sortilin的X射线结构，但小鼠IFNα的结构仍然未知。在本研究中，我们确定了小鼠IFNα2的晶体结构在2.1 nm分辨率，并研究了其与分拣蛋白的相互作用。对接模拟表明，小鼠IFNα2的Arg 22对于与小鼠分拣蛋白的相互作用是重要的。通过流式细胞术测定，Arg 22突变为丙氨酸促进IFNα2分泌，突出了该残基对与分拣蛋白相互作用的贡献。这些结果表明Arg 22在小鼠IFNα中对于分拣蛋白介导的IFNα运输具有重要作用。
Interferon α (IFNα) is a type I interferon, an essential cytokine employed by the immune system to fight viruses. Although a number of the structures of type I interferons have been reported, most of the known structures of IFNα are in complex with its receptors. There are only two examples of structures of free IFNα: one is a dimeric X-ray structure without side-chain information; and another is an NMR structure of human IFNα. Although we have shown that Sortilin is involved in the secretion of IFNα, the details of the molecular interaction and the secretion mechanism remain unclear. Recently, we solved the X-ray structure of mouse Sortilin, but the structure of mouse IFNα remained unknown. In this study, we determined the crystal structure of mouse IFNα2 at 2.1 Å resolution and investigated its interaction with Sortilin. Docking simulations suggested that Arg22 of mouse IFNα2 is important for the interaction with mouse Sortilin. Mutation of Arg22 to alanine facilitated IFNα2 secretion, as determined by flow cytometry, highlighting the contribution of this residue to the interaction with Sortilin. These results suggest an important role for Arg22 in mouse IFNα for Sortilin-mediated IFNα trafficking.