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

Abstract

At the center of iron and oxidant metabolism is the ferritin superfamily: protein cages with Fe2+ ion channels and catalytic di- Fe/O redox centers that initiate 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, to 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 Fe2+/O2 catalysis and mineral crystallinity. The relatively low mineral order in liver ferritin, for example, coincides with a high % of L subunits, and, thus, a low % 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), the nanocage pores (iron chelation in therapeutic hypertransfusion), the mRNA noncoding, IRE-riboregulator (normalizing ferritin iron content after therapeutic hypertransfusion, and as protein nanovessels to deliver medicinal or sensor cargo.

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…Storage and detoxification of iron represent the main functions of these molecules, and much work has been done to understand the chemical and molecular details of this processes in the different types of ferritins, the classical ones, the heme-containing bacterioferritins and the smaller docecameric Dps proteins. These findings have been described in various excellent reviews of the recent years (Arosio and Levi 2010;Bou-Abdallah 2010;Theil 2013), but the interest in ferritin is not fading and new interesting data are continuously appearing. In this review we focus our attention to the mammalian ferritins and their possible involvement in the perturbation of iron homeostasis often observed in neurodegenerative disorders.…”

Genetic and biochemical investigations of the role of MamP in redox control of iron biomineralization inMagnetospirillum magneticum

“…After proteolytic digestion, the sample was subjected to a second passage over a Ni-NTA column and an amylose column to remove His 6 .TEV protease, His 6 .MBP, and other cellular proteins enriched by Ni-NTA chromatography. The lingering minor contaminants were then removed by size-exclusion chromatography, yielding MamP which is >95% pure as judged by an overloaded reducing gel (SI Appendix, Fig.…”

“…The mineralization of calcium is the most well understood as it produces perhaps the largest class of biominerals (1,2). However, the controlled mineralization of elements such as silicon (4), iron (5,6), copper (7), and manganese (8) is also observed, although less broadly distributed. Of the latter group, iron biomineralization by magnetotactic bacteria represents a particularly interesting case for understanding how the production of nanomaterials can be programmed at the genetic level.…”

Iron management and production of electricity by microorganisms

“…In humans, the mechanistic differences found between variations of this protein helped us to understand that different organs have different types of ferritins. While tissues with high oxygen levels such as cardiac and erythroid cells mostly have H-type rich ferritins, a fast and more effective protein towards iron oxidation, tissues with slower iron turnover such as the liver have predominantly L-type rich ferritins which are less effective regarding the iron oxidation mechanism (Pereira et al 1998;Pereira et al 1997;Theil 2013;Theil et al 2013).…”