Crystal Structure of Human Frataxin

Dhe-Paganon, Sirano; Shigeta, Ron; Chi, Young-In; Ristow, Michael; Shoelson, Steven E.

doi:10.1074/jbc.c000407200

Cited by 226Enzyme Structure and FunctionGenetic Neurodegenerative DiseasesProtein Structure and Dynamics

Crystal Structure of Human Frataxin

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Dhe-Paganon, Sirano, Shigeta, Ron, Chi, Young-In, Ristow, Michael, Shoelson, Steven E.·2000·Journal of Biological Chemistry

DOI 10.1074/jbc.c000407200

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Abstract

Friedreich's ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The structure of human frataxin, which we have determined at 1.8-A resolution, reveals a novel protein fold. A five-stranded, antiparallel beta sheet provides a flat platform, which supports a pair of parallel alpha helices, to form a compact alphabeta sandwich. A cluster of 12 acidic residues from the first helix and the first strand of the large sheet form a contiguous anionic surface on the protein. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Additional conserved residues create an extended 1008-A(2) patch on a distinct surface of the protein. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein-iron binding.

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Exogenous Fpn expressed in Xenopus oocytes served as a ferrous iron exporter.
“Exogenous Fpn expressed in Xenopus oocytes served as a ferrous iron exporter (72).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [72]
Fpn is abundantly expressed on the basolateral membrane of polarized enterocytes in the duodenum, in the cytosol of reticuloendothelial cells, and on the basal surface of syncytiotrophoblasts of the placenta.
“Simultaneous studies characterized Fpn, which is abundantly expressed on the basolateral membrane of polarized enterocytes in the duodenum, in the cytosol of reticuloendothelial cells, and on the basal surface of syncytiotrophoblasts of the placenta (1, 72, 198).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [72]
Fpn was originally identified by positional cloning to identify the causative gene for hypochromic anemia of weissherbst mutant zebrafish.
“Fpn (also termed Ireg1, MTP1) was originally identified by positional cloning to identify the causative gene for hypochromic anemia of “weissherbst” mutant zebrafish (72).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [72]

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Towards a structural understanding of Friedreich’s ataxia: the solution structure of frataxin
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Authors: Dhe-Paganon, S., Shigeta, R., Chi, Y.-I., Ristow, M., & Shoelson, S. E.
Affiliations: Joslin Diabetes Center (US)
Corresponding author: Shoelson, Steven E.
ORCID: Shigeta, Ron
Chi, Young-In
Ristow, Michael
Shoelson, Steven E.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2000-10
Volume: 275
Issue: 40
Pages: 30753-30756
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.c000407200
OpenAlex: W2105822562
Cited by: 226
References: 32
Citations by year: 2026: 4 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 6 · 2020: 10 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 4 · 2015: 9 · 2014: 10 · 2013: 14 · 2012: 3
FWCI: 8.76
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7312 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Joslin Diabetes Center
Universität zu Köln
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (DK4312, DK07260, T32DK007260)
Topics: Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords: frataxin, Friedreich's ataxia, protein crystal structure, novel protein fold, anionic surfaces, disease-associated mutations, protein-protein interaction, hydrophobic core
MeSH terms: Frataxin, Amino Acid Sequence, Cloning, Molecular, Friedreich Ataxia, Humans, Iron, Models, Molecular, Molecular Sequence Data, Protein Binding, Mutagenesis, Site-Directed, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Folding, Phosphotransferases (Alcohol Group Acceptor), Crystallography, X-Ray, Iron-Binding Proteins

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Crystal Structure of Human Frataxin

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