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Mol Cell. 2020 Apr 2;78(1):31-41.e5. doi: 10.1016/j.molcel.2020.02.011. Epub 2020 Mar 2.

FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.

Author information

1
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
2
Division of Hematology and Hematologic Malignancies and Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA.
3
Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
4
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; NYU Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
5
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; NYU Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
6
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: nzheng@uw.edu.

Abstract

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 stateĀ 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.

KEYWORDS:

FBXL5; IRP2; cryo-EM; iron homeostasis; iron-sulfur cluster; oxygen-responsive

Conflict of interest statement

Declaration of Interests N.Z. is a member of the scientific advisory board of Kymera Therapeutics and a co-founder of Coho Therapeutics. M.P. is a consultant for BeyondSpring Pharmaceutics and a member of the scientific advisory board of Kymera Therapeutics and Cullgen Therapeutics. The authors declare no other competing interests.

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