+Search query
-Structure paper
Title | FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster. |
---|---|
Journal, issue, pages | Mol Cell, Vol. 78, Issue 1, Page 31-41.e5, Year 2020 |
Publish date | Apr 2, 2020 |
![]() | 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 / ![]() |
PubMed 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 ...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. |
![]() | ![]() ![]() ![]() |
Methods | EM (single particle) |
Resolution | 3.0 Å |
Structure data | EMDB-21149, PDB-6vcd: |
Chemicals | ![]() ChemComp-FES: |
Source |
|
![]() | ![]() ![]() ![]() |