Iron-mediated aggregation and a localized structural change characterize ferritin from a mutant light chain polypeptide that causes neurodegeneration

Martin A. Baraibar, Ana G. Barbeito, Barry B. Muhoberac, Ruben Vidal

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38 Citations (Scopus)

Abstract

Nucleotide insertions in the ferritin light chain (FTL) polypeptide gene cause hereditary ferritinopathy, a neurodegenerative disease characterized by abnormal accumulation of ferritin and iron in the central nervous system. Here we describe for the first time the protein structure and iron storage function of the FTL mutant p.Phe167SerfsX26 (MT-FTL), which has a C terminus altered in sequence and extended in length. MT-FTL polypeptides assembled spontaneously into soluble, spherical 24-mers that were ultrastructurally indistinguishable from those of the wild type. Far-UVCDshowed a decrease in α-helical content, and 8-anilino-1-naphthalenesulfonate fluorescence revealed the appearance of hydrophobic binding sites. Near-UV CD and proteolysis studies suggested little or no structural alteration outside of the C-terminal region. In contrast to wild type, MT-FTL homopolymers precipitated at much lower iron loading, had a diminished capacity to incorporate iron, and were less thermostable. However, precipitation was significantly reversed by addition of iron chelators both in vitro and in vivo. Our results reveal substantial protein conformational changes localized at the 4-fold pore of MT-FTL homopolymers and imply that the C terminus of the MT-FTL polypeptide plays an important role in ferritin solubility, stability, and iron management. We propose that the protrusion of some portion of the C terminus above the spherical shell allows it to cross-link with other mutant polypeptides through iron bridging, leading to enhanced mutant precipitation by iron. Our data suggest that hereditary ferritinopathy pathogenesis is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates.

Original languageEnglish
Pages (from-to)31679-31689
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number46
DOIs
StatePublished - Nov 14 2008

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Ferritins
Apoferritins
Agglomeration
Iron
Light
Peptides
Homopolymerization
Neurodegenerative diseases
Proteolysis
Neurology
Chelating Agents
Neurodegenerative Diseases
Solubility
Toxicity
Proteins
Nucleotides
Central Nervous System
Genes
Fluorescence
Binding Sites

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Iron-mediated aggregation and a localized structural change characterize ferritin from a mutant light chain polypeptide that causes neurodegeneration. / Baraibar, Martin A.; Barbeito, Ana G.; Muhoberac, Barry B.; Vidal, Ruben.

In: Journal of Biological Chemistry, Vol. 283, No. 46, 14.11.2008, p. 31679-31689.

Research output: Contribution to journalArticle

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