6VCD

Cryo-EM structure of IRP2-FBXL5-SKP1 complex

Summary for 6VCD

• Entry DOI: 10.2210/pdb6vcd/pdb
• EMDB information: 21149
• Descriptor: Iron-responsive element binding protein 2, isoform CRA_a, F-box/LRR-repeat protein 5, S-phase kinase-associated protein 1, ... (4 entities in total)
• Functional Keywords: e3 ligase, [2fe-2s] cluster, iron metabolism, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 178853.55

Authors

Wang, H.,Shi, H.,Zheng, N. (deposition date: 2019-12-20, release date: 2020-08-05, Last modification date: 2024-03-06)

Primary citation

Wang, H.,Shi, H.,Rajan, M.,Canarie, E.R.,Hong, S.,Simoneschi, D.,Pagano, M.,Bush, M.F.,Stoll, S.,Leibold, E.A.,Zheng, N.
FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.
Mol.Cell, 78:31-41.e5, 2020

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 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.

PubMed: 32126207
DOI: 10.1016/j.molcel.2020.02.011

Experimental method

ELECTRON MICROSCOPY (3 Å)