The Structures of Frataxin Oligomers Reveal the Mechanism for the Delivery and Detoxification of Iron
Open accessAbstract
Defects in the mitochondrial protein frataxin are responsible for Friedreich ataxia, a neurodegenerative and cardiac disease that affects 1:40,000 children. Here, we present the crystal structures of the iron-free and iron-loaded frataxin trimers, and a single-particle electron microscopy reconstruction of a 24 subunit oligomer. The structures reveal fundamental aspects of the frataxin mechanism. The trimer has a central channel in which one atom of iron binds. Two conformations of the channel with different metal-binding affinities suggest that a gating mechanism controls whether the bound iron is delivered to other proteins or transferred to detoxification sites. The trimer constitutes the basic structural unit of the 24 subunit oligomer. The architecture of this oligomer and several features of the trimer structure demonstrate striking similarities to the iron-storage protein ferritin. The data reveal how stepwise assembly provides frataxin with the structural flexibility to perform two functions: metal delivery and detoxification.
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A point mutation in the IRE consensus sequence is in ferritin H mRNA in a family with dominant iron-loading disorder.
“It was revealed that a point mutation in the IRE consensus sequence is in ferritin H mRNA in a family with dominant iron-loading disorder (154).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [154]
Expression of the IRE mutant enhanced translational repression of ferritin H.
“Expression of the IRE mutant enhanced translational repression of ferritin H (154).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [154]
An A to U transition at position 49 was associated with an increased affinity for IRP compared with the wild type.
“This A to U transition at position 49 was associated with an increased affinity for IRP compared with the wild type.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [154]
Another form of hereditary iron overload results from mutation of the IRE in ferritin H mRNA and results in an autosomal-dominant iron-overload disorder.
“Another form of hereditary iron overload results from mutation of the IRE in ferritin H mRNA and results in an autosomal-dominant iron-overload disorder.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [154]
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- Authors
- Karlberg, T., Schagerlöf, U., Gakh, O., Park, S., Ryde, U., Lindahl, M., Leath, K., Garman, E., Isaya, G., & Al-Karadaghi, S.
- Affiliations
- Lund University (SE)
- Mayo Clinic (US)
- University of Oxford (GB)
- Corresponding author
- Isaya, Grazia
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 14
- Issue
- 10
- Pages
- 1535-1546
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2094754882
- Cited by
- 85
- References
- 56
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1 · 2018: 1 · 2017: 7 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 6
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2481 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Vetenskapsrådet
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- frataxin, Friedreich's ataxia, iron delivery, iron detoxification, gating mechanism, metal binding affinity, mitochondrial iron metabolism, protein assembly
- MeSH terms
- Frataxin, Amino Acid Sequence, Biological Transport, Iron, Microscopy, Electron, Models, Molecular, Molecular Sequence Data, Mutation, Protein Binding, Protein Conformation, Crystallography, X-Ray, Mitochondrial Proteins, Saccharomyces cerevisiae Proteins, Iron-Binding Proteins
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