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Cited by 113Iron Metabolism and DisordersEnzyme Structure and FunctionMetal-Catalyzed Oxygenation Mechanisms

Crystal Structure and Biochemical Properties of the Human Mitochondrial Ferritin and its Mutant Ser144Ala

Langlois d'Estaintot, Béatrice, Santambrogio, Paolo, Granier, Thierry, Gallois, Bernard, Chevalier, Jean Marc, Précigoux, Gilles, Levi, Sonia, Arosio, Paolo·2004·Journal of Molecular Biology
DOI 10.1016/j.jmb.2004.04.036
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Abstract

Mitochondrial ferritin is a recently identified protein precursor encoded by an intronless gene. It is specifically taken up by the mitochondria and processed to a mature protein that assembles into functional ferritin shells. The full mature recombinant protein and its S144A mutant were produced to study structural and functional properties. They yielded high quality crystals from Mg(II) solutions which diffracted up to 1.38 Angstrom resolution. The 3D structures of the two proteins resulted very similar to that of human H-ferritin, to which they have high level of sequence identity (approximately 80%). Metal-binding sites were identified in the native crystals and in those soaked in Mn(II) and Zn(II) solutions. The ferroxidase center binds binuclear iron at the sites A and B, and the structures showed that the A site was always fully occupied by Mg(II), Mn(II) or Zn(II), while the occupancy of the B site was variable. In addition, distinct Mg(II) and Zn(II)-binding sites were found in the 3-fold axes to block the hydrophilic channels. Other metal-binding sites, never observed before in H-ferritin, were found on the cavity surface near the ferroxidase center and near the 4-fold axes. Mitochondrial ferritin showed biochemical properties remarkably similar to those of human H-ferritin, except for the difficulty in renaturing to yield ferritin shells and for a reduced ( approximately 41%) rate in ferroxidase activity. This was partially rescued by the substitution of the bulkier Ser144 with Ala, which occurs in H-ferritin. The residue is exposed on a channel that connects the ferroxidase center with the cavity. The finding that the mutation increased both catalytic activity and the occupancy of the B site demonstrated that the channel is functionally important. In conclusion, the present data define the structure of human mitochondrial ferritin and provide new data on the iron pathways within the H-type ferritin shell.

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  • Global deletion of IRP2 in mice manifests in aberrant accumulation of iron within the brain that correlates with tremor and movement disorders such as bradykinesia and ataxia.

    “Global deletion of IRP2 in mice manifested in aberrant accumulation of iron within the brain that correlated with tremor, and movement disorders such as bradykinesia and ataxia (175) (Table 4).”

    From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [175]

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Authors
Langlois d'Estaintot, B., Santambrogio, P., Granier, T., Gallois, B., Chevalier, J. M., Précigoux, G., Levi, S., & Arosio, P.
Affiliations
  • IRCCS Ospedale San Raffaele (IT)
  • Université Bordeaux-I (FR)
  • University of Brescia (IT)
Corresponding author
Arosio, Paolo
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2004-07
Volume
340
Issue
2
Pages
277-293
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2004.04.036
OpenAlex
W2079886123
Cited by
113
References
43
Citations by year
2026: 1 · 2025: 4 · 2024: 1 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 6 · 2013: 6 · 2012: 3
FWCI
3.14
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords
mitochondrial ferritin, crystal structure, ferroxidase center, metal binding sites, ferroxidase activity, intronless genes, protein folding, iron transport
MeSH terms
Amino Acid Sequence, Binding Sites, Ferritins, Humans, Manganese, Mitochondria, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Denaturation, Serine, Zinc, Mutagenesis, Sequence Homology, Amino Acid, Crystallography, X-Ray

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