ArticleMolecular cell2020
FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.
Article in Molecular cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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96 citing papers in PubMed, 192 citations in OpenAlex.
- The role of iron in normal and impaired testicular function.Andrology · 2026Review
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- FBXL5 depletion as a novel strategy against osteosarcoma: Evidence for MEK/ERK inhibition and enhanced therapeutic sensitivity.Oncology letters · 2026Article
- Iron homeostasis disruption and lipid peroxidation in skeletal muscle during short-term immobilization.FEBS open bio · 2026Article
- Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.HGG advances · 2026Article
- In vivo visualization of bioactive iron and oxygen using LiON, the labile iron and oxygen notifier.Cell reports methods · 2026Article
- Coenzyme A mitigates cystine-deprivation-induced ferroptosis by suppressing the iron-starvation response.The FEBS journal · 2026Article
- Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.Nature communications · 2026Article
- Iron Dysregulation and Vascular Diseases: A Contemporary Review.Journal of the American Heart Association · 2026Review
- Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives.iScience · 2026Review
- Redox cycling nitroxide limits cellular iron availability and selectively inhibits iron-sulfur cluster metabolism.Cell death discovery · 2026Article
- Degrons and degradation signals beyond short linear motifs.Nature chemical biology · 2026Review
- Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis.iScience · 2026Article
- Rapid genome modifications including chromosomal fusions and large-scale inversions are key features in Arctic codfish species.Genome biology · 2026Article
- Client recruitment mechanism of the cytosolic Fe-S cluster assembly targeting complex.The EMBO journal · 2026Article
- Iron: Regulation, redox homeostasis, and ferroptosis in cancer.Ferroptosis and oxidative stress · 2026Article
- Bioinformatics analysis and qRT-PCR validation of iron metabolism-related genes in pediatric asthma.PloS one · 2026Article
- Integration analysis of single-cell and spatial transcriptomics identifies prognostic genes associated with neddylation in colorectal cancer.Discover oncology · 2025Article
- Ferroptosis-Mediated Cell-Specific Damage: Molecular Cascades and Therapeutic Breakthroughs in Diabetic Retinopathy.Antioxidants (Basel, Switzerland) · 2025Review
- Integrative biochemical and computational analysis of leflunomide-induced redox alterations in Nauphoeta cinerea.Scientific reports · 2025Article
36 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.