further probed with five peptides identified from a combinatorial phage display
library of 10
9 peptides that bound to wild-type ferritin (Liu et al. 2007). One of the
five binding peptides increased iron release as if it were unfolding the pores. Such
results lead to the hypothesis that cellular proteins control folding/unfolding of
ferritin pores and, thereby, control ferritin mineral/reductant/chelator interactions
in vivo (Liu et al. 2003).
2.5.1 Perspectives
Ferritin protein nanocages, which synthesize hydrated iron oxide biominerals and
protect them from uncontrolled cell reductants, are ubiquitous. Recognizable
sequences are found in archaea, bacteria, plants, and animals, including humans.
Ferritins concentrate iron in biominerals containing thousands of iron and oxygen
atoms, to match cell need and to act as antioxidants that prevent corrosive ROS
(reactive oxygen species) release from iron and dioxygen or hydrogen peroxide
chemistry. Ferritin plays a role in normal development and in disease, as pathogens
and host battle with iron and inflammatory oxidants. Hallmarks of ferritin family
members are a quaternary protein cage structure self-assembled from polypeptide
subunits and studded with: (1) catalytic sites that initiate mineralization, (2) pores
that control iron entry and mineral reduction/dissolution, and (3) internal channels
that facilitate during mineral nucleation. Ferritin subunits fold into 4 a-helix
bundles; 12 subunit structures are mini-ferritins (Dps proteins), and 24 subunit
structures are maxi-ferritins. The variable phosphate content of ferritin biominerals
appears to relate to differences in environmental phosphate during biomineral
synthesis. High-phosphate-induced minerals have biological relevance in plants
and bacteria while biomineral disorder in low phosphate ion biominerals of animals
depends on the relative abundance in the protein cage of subunits that are catalytically inactive (L subunits). The wide divergence among ferritin amino acid
sequences has two implications for future research: First, solving the self-assembly
code for the cage, pores, and active sites will require new dimensions in informatics. Second, ferritins that escape identification by scanning methods emphasizing
primary structure will be trapped by future scanning methods that incorporate
features of secondary and tertiary structures to reveal more ferritin genes. Finally,
the paucity of current information about the full role of the ferritin cage in
biomineral synthesis, beyond catalysis and mineral nucleation, which is hampered
by the sequence divergence, has obscured the answer to the question of the role of
the protein cage in formation of the bulk biomineral. Clearly, the rapid advances in
understanding function, structure, and biological importance of ferritin protein
cages and iron biominerals still leave many questions for the future.
Acknowledgment The authors are grateful for the contributions of all the members of the Theil
Group. The writing of the manuscript and work described herein were supported by the CHORI
Foundation (ECT), the NIH (DK20251) (LB and ECT), and a Rubicon Fellowship from the
Netherlands Organization for Scientific Research (NWO), (LB).
44
L.E. Bevers and E.C. Theil
library of 10
9 peptides that bound to wild-type ferritin (Liu et al. 2007). One of the
five binding peptides increased iron release as if it were unfolding the pores. Such
results lead to the hypothesis that cellular proteins control folding/unfolding of
ferritin pores and, thereby, control ferritin mineral/reductant/chelator interactions
in vivo (Liu et al. 2003).
2.5.1 Perspectives
Ferritin protein nanocages, which synthesize hydrated iron oxide biominerals and
protect them from uncontrolled cell reductants, are ubiquitous. Recognizable
sequences are found in archaea, bacteria, plants, and animals, including humans.
Ferritins concentrate iron in biominerals containing thousands of iron and oxygen
atoms, to match cell need and to act as antioxidants that prevent corrosive ROS
(reactive oxygen species) release from iron and dioxygen or hydrogen peroxide
chemistry. Ferritin plays a role in normal development and in disease, as pathogens
and host battle with iron and inflammatory oxidants. Hallmarks of ferritin family
members are a quaternary protein cage structure self-assembled from polypeptide
subunits and studded with: (1) catalytic sites that initiate mineralization, (2) pores
that control iron entry and mineral reduction/dissolution, and (3) internal channels
that facilitate during mineral nucleation. Ferritin subunits fold into 4 a-helix
bundles; 12 subunit structures are mini-ferritins (Dps proteins), and 24 subunit
structures are maxi-ferritins. The variable phosphate content of ferritin biominerals
appears to relate to differences in environmental phosphate during biomineral
synthesis. High-phosphate-induced minerals have biological relevance in plants
and bacteria while biomineral disorder in low phosphate ion biominerals of animals
depends on the relative abundance in the protein cage of subunits that are catalytically inactive (L subunits). The wide divergence among ferritin amino acid
sequences has two implications for future research: First, solving the self-assembly
code for the cage, pores, and active sites will require new dimensions in informatics. Second, ferritins that escape identification by scanning methods emphasizing
primary structure will be trapped by future scanning methods that incorporate
features of secondary and tertiary structures to reveal more ferritin genes. Finally,
the paucity of current information about the full role of the ferritin cage in
biomineral synthesis, beyond catalysis and mineral nucleation, which is hampered
by the sequence divergence, has obscured the answer to the question of the role of
the protein cage in formation of the bulk biomineral. Clearly, the rapid advances in
understanding function, structure, and biological importance of ferritin protein
cages and iron biominerals still leave many questions for the future.
Acknowledgment The authors are grateful for the contributions of all the members of the Theil
Group. The writing of the manuscript and work described herein were supported by the CHORI
Foundation (ECT), the NIH (DK20251) (LB and ECT), and a Rubicon Fellowship from the
Netherlands Organization for Scientific Research (NWO), (LB).
44
L.E. Bevers and E.C. Theil