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, 52 (21), 12223-33

Ferritin: The Protein Nanocage and Iron Biomineral in Health and in Disease


Ferritin: The Protein Nanocage and Iron Biomineral in Health and in Disease

Elizabeth C Theil. Inorg Chem.


At the center of iron and oxidant metabolism is the ferritin superfamily: protein cages with Fe(2+) ion channels and two catalytic Fe/O redox centers that initiate the formation of caged Fe2O3·H2O. Ferritin nanominerals, initiated within the protein cage, grow inside the cage cavity (5 or 8 nm in diameter). Ferritins contribute to normal iron flow, maintenance of iron concentrates for iron cofactor syntheses, sequestration of iron from invading pathogens, oxidant protection, oxidative stress recovery, and, in diseases where iron accumulates excessively, iron chelation strategies. In eukaryotic ferritins, biomineral order/crystallinity is influenced by nucleation channels between active sites and the mineral growth cavity. Animal ferritin cages contain, uniquely, mixtures of catalytically active (H) and inactive (L) polypeptide subunits with varied rates of Fe(2+)/O2 catalysis and mineral crystallinity. The relatively low mineral order in liver ferritin, for example, coincides with a high percentage of L subunits and, thus, a low percentage of catalytic sites and nucleation channels. Low mineral order facilitates rapid iron turnover and the physiological role of liver ferritin as a general iron source for other tissues. Here, current concepts of ferritin structure/function/genetic regulation are discussed and related to possible therapeutic targets such as mini-ferritin/Dps protein active sites (selective pathogen inhibition in infection), nanocage pores (iron chelation in therapeutic hypertransfusion), mRNA noncoding, IRE riboregulator (normalizing the ferritin iron content after therapeutic hypertransfusion), and protein nanovessels to deliver medicinal or sensor cargo.


Fig. 1
Fig. 1. Ferritin protein
A. X-section of a eukaryotic ferritin protein cage, viewed with a 3-fold symmetry axis pore centered in the mineral growth cavityS. B. A ferritin protein subunit: metal ion traffic (white arrows); in a ; protein cocrystal with Mg2+ -green sphere; Co2+ -pink sphere; in channel at left. C. Progress curves of Fe2+/O2 catalysis: Fe3+-O-O-Fe3+ (DFP, λmax-650 nm-blue; Fe3+O broad absorbance, A350nm-red. D. N-terminal extension: R72D, left, N-terminus disordered; WT, right,-N-terminus-pink; helix numbers: 1,2,3,4. Fe2+ exit from ferritin mineral is accelerated in R72D,. Figure panels contributed by T. Tosha and R. K. Behera, using PDB 3KA4,PDB 3DE1 and Pymol.
Fig. 2
Fig. 2. Protein control of ferritin mineral dissolution/Fe2+chelation rates
Two heptapeptides selectively targeted to ferritin pore structure were isolated from a heptapetide library (109 peptides) and altered WT mineral dissolution and Fe2+ exit rates. Left: Fe2+ exit/chelation progress curves: green=peptide 1; blue-peptide 2; black-no peptide. Right: Structures of ferritin protein cage- blue: pore sequences: WT, folded-tan; L134P-unfolded-red. View: 3-fold symmetry axis is centered. Ferritin mineral dissolution : NADH/FMN – reductant; Fe2+ bipyridyl- rate of Fe2+ exit. This research was originally published in the Journal of Biological Chemistry 2007, volume 282, page 31821, 2007.
Fig 3
Fig 3. Differences mineral order among human tissue ferritins coincide with differences in the numbers of catalytic centers and nucleation channels/cage
Ferritin protein cages rich in H subunits and with highly ordered ferritin minerals, are found in tissues with high oxygenase, such as heart, while ferritin protein cages rich in L subunits and with relatively disordered minerals, are found in human liver. The supply of stored iron to other tissues is a major function of liver ferritin, which is facilitated by the high surface/volume of the more disordered ferritin mineral.

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