Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5)
Open accessAbstract
Mammalian cells maintain iron homeostasis by sensing changes in bioavailable iron levels and promoting adaptive responses. FBXL5 is a subunit of an E3 ubiquitin ligase complex that mediates the stability of iron regulatory protein 2, an important posttranscriptional regulator of several genes involved in iron metabolism. The stability of FBXL5 is regulated in an iron- and oxygen-responsive manner, contingent upon the presence of its N-terminal domain. Here we present the atomic structure of the FBXL5 N terminus, a hemerythrin-like α-helical bundle fold not previously observed in mammalian proteins. The core of this domain employs an unusual assortment of amino acids necessary for the assembly and sensing properties of its diiron center. These regulatory features govern the accessibility of a mapped sequence required for proteasomal degradation of FBXL5. Detailed molecular and structural characterization of the ligand-responsive hemerythrin domain provides insights into the mechanisms by which FBXL5 serves as a unique mammalian metabolic sensor.
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When iron levels are low, FBXL5 is degraded due to its Fe-binding N-terminal hemerythrin-like iron-sensing domain undergoing a conformational change, leading to FBXL5 polyubiquitination and degradation, resulting in IRP2 accumulation.
“However, when iron levels are low, FBXL5 is itself degraded. This is due to a Fe-binding N-terminal hemerythrin-like (Hr) iron-sensing domain in FBXL5. The Hr domain undergoes a conformational change when iron is not present—this structural change leads to FBXL5 polyubiquitination and degradation resulting in IRP2 accumulation (Thompson et al., 2012).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Thompson et al., 2012
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References 42 · Cited by 71
Research works printed but not linked: 1
- Otwinowski, Z. (1991) in Proceedings of the CCP4 Study Weekend (Wolf, W., Evans, P. R., and Leslie, A. G. W. eds) pp. 80 -86, Science and Engi- neering Research Council, Cambridge, UK
- Authors
- Thompson, J. W., Salahudeen, A. A., Chollangi, S., Ruiz, J. C., Brautigam, C. A., Makris, T. M., Lipscomb, J. D., Tomchick, D. R., & Bruick, R. K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Minnesota (US)
- Corresponding author
- Bruick, Richard K.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 287
- Issue
- 10
- Pages
- 7357-7365
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3293540
- OpenAlex
- W1990120691
- Cited by
- 71
- References
- 42
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 10 · 2013: 3 · 2012: 6
- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, DE-AC02-)
- Burroughs Wellcome Fund
- Welch Foundation (I-1568)
- McKnight Foundation
- University of Chicago (DE-AC02-06CH11357)
- National Institutes of Health (DE-AC02–06CH11357)
- National Heart, Lung, and Blood Institute (HL102481, R01HL102481)
- National Institute of General Medical Sciences (GM24689, R01GM024689)
- National Center for Research Resources (C06RR015437, C06 RR 15437-01))
- Biological and Environmental Research (Contract DE-AC02-06CH11357, DEAC0206CH11357)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, Contract DE-AC02-06CH11357, 06CH11357)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- FBXL5, iron sensing, iron homeostasis, diiron center, E3 ubiquitin ligase, IRP2, protein stability, proteasomal degradation, protein structure, leucine-rich repeat proteins
- MeSH terms
- Enzyme Stability, Humans, Structure-Activity Relationship, Protein Structure, Tertiary, Crystallography, X-Ray, Iron Regulatory Protein 2, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, F-Box Proteins, Proteasome Endopeptidase Complex, Proteolysis
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