Institute of Quantum Beam Science, Graduate School of Science and Engineering, Ibaraki University, 4-12-1 Nakanarusawa, Hitachi, Ibaraki 316-8511, Japan.
Frontier Research Center for Applied Atomic Sciences, Ibaraki University, 162-1 Shirakata, Tokai Naka, Ibaraki 319-1106, Japan.
J Biochem. 2021 Oct 11;170(2):265-273. doi: 10.1093/jb/mvab038.
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.
干扰素 α（IFNα）是一种 I 型干扰素，是免疫系统用来对抗病毒的必需细胞因子。虽然已经报道了许多 I 型干扰素的结构，但大多数已知的 IFNα 结构都与其受体形成复合物。只有两种游离 IFNα 的结构示例：一种是没有侧链信息的二聚体 X 射线结构；另一种是人类 IFNα 的 NMR 结构。虽然我们已经表明 Sortilin 参与了 IFNα 的分泌，但分子相互作用和分泌机制的细节仍不清楚。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。在这项研究中，我们确定了 2.1Å 分辨率的小鼠 IFNα2 的晶体结构，并研究了它与 Sortilin 的相互作用。对接模拟表明，小鼠 IFNα2 的 Arg22 对于与小鼠 Sortilin 的相互作用很重要。通过流式细胞术确定，Arg22 突变为丙氨酸促进了 IFNα2 的分泌，这突出了该残基对与 Sortilin 相互作用的贡献。这些结果表明 Arg22 在小鼠 IFNα 中对于 Sortilin 介导的 IFNα 转运具有重要作用。
