FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster
FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster
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DOI：
10.1016/j.molcel.2020.02.011
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发表时间：
2020-04-02
期刊：
影响因子：
16
通讯作者：
Zheng，Ning
中科院分区：
文献类型：
--
作者：
Wang，Hui;Shi，Hui;Zheng，Ning
细胞铁稳态由FBXL 5介导的铁调节蛋白2（IRP 2）降解主导，IRP 2依赖于铁和氧。然而，FBXL 5和IRP 2之间的物理相互作用如何调节仍然是难以捉摸的。在这里，我们表明，FBXL 5的C-末端底物结合域在氧化状态下含有一个[2Fe 2S]簇。IRP 2-FBXL 5-SKP 1复合物的冷冻电子显微镜（cryo-EM）结构显示，该簇组织了负责募集IRP 2的FBXL 5 C-末端环。有趣的是，IRP 2与FBXL 5的结合取决于由环境氧维持的[2Fe 2S]簇的氧化状态，这可以解释缺氧诱导的IRP 2稳定。空间不相容性还允许FBXL 5从铁响应元件RNA物理地驱逐IRP 2以促进其周转。总之，我们的研究已经确定了FBXL 5内的铁硫簇，其促进IRP 2多聚泛素化和降解，以响应铁和氧浓度。
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.