Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Division of Hematology and Hematologic Malignancies and Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
Mol Cell. 2020 Apr 2;78(1):31-41.e5. doi: 10.1016/j.molcel.2020.02.011. Epub 2020 Mar 2.
Cellular iron homeostasis is dominated by FBXL5-mediated degradation of iron regulatory protein 2 (IRP2), which is dependent on both iron and oxygen. However, how the physical interaction between FBXL5 and IRP2 is regulated remains elusive. Here, we show that the C-terminal substrate-binding domain of FBXL5 harbors a [2Fe2S] cluster in the oxidized state. A cryoelectron microscopy (cryo-EM) structure of the IRP2-FBXL5-SKP1 complex reveals that the cluster organizes the FBXL5 C-terminal loop responsible for recruiting IRP2. Interestingly, IRP2 binding to FBXL5 hinges on the oxidized state of the [2Fe2S] cluster maintained by ambient oxygen, which could explain hypoxia-induced IRP2 stabilization. Steric incompatibility also allows FBXL5 to physically dislodge IRP2 from iron-responsive element RNA to facilitate its turnover. Taken together, our studies have identified an iron-sulfur cluster within FBXL5, which promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations.
细胞内铁稳态由 FBXL5 介导的铁调节蛋白 2 (IRP2) 降解所主导，该过程依赖于铁和氧。然而，FBXL5 和 IRP2 之间的物理相互作用如何受到调控仍不清楚。在这里，我们发现 FBXL5 的 C 端底物结合域在氧化状态下含有一个 [2Fe2S] 簇。IRP2-FBXL5-SKP1 复合物的低温电子显微镜 (cryo-EM) 结构表明，该簇组织了 FBXL5 C 端环，负责招募 IRP2。有趣的是，IRP2 与 FBXL5 的结合取决于周围氧维持的 [2Fe2S] 簇的氧化状态，这可以解释低氧诱导的 IRP2 稳定。空间不相容性也允许 FBXL5 将 IRP2 从铁反应元件 RNA 上物理排斥，从而促进其周转。总之，我们的研究在 FBXL5 内鉴定了一个铁硫簇，该簇促进 IRP2 的多泛素化和降解，以响应铁和氧浓度的变化。
