生物
星团(航天器)
泛素
氧气
细胞生物学
平衡
铁硫簇
生物物理学
生物化学
化学
酶
计算机科学
基因
有机化学
程序设计语言
作者
Hui Wang,Hui Shi,Malini Rajan,Elizabeth R. Canarie,Seoyeon Hong,Daniele Simoneschi,Michele Pagano,Matthew F. Bush,Stefan Stoll,Elizabeth A. Leibold,Ning Zheng
出处
期刊:Molecular Cell
[Elsevier]
日期:2020-04-01
卷期号:78 (1): 31-41.e5
被引量:109
标识
DOI:10.1016/j.molcel.2020.02.011
摘要
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.
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