Ferritin is a widespread protein found in almost all living organisms, including animals, plants, and bacteria. It functions as the primary protein for storing iron, helping to maintain iron balance within cells and the body. Ferritin ensures that iron is available when needed while also preventing its harmful effects, as excess iron can generate damaging reactive oxygen species.
The Ferritin Protein Shell
The ferritin molecule features a distinctive hollow, spherical cage-like architecture. This protein shell is formed by the self-assembly of typically 24 polypeptide subunits. These subunits arrange themselves into a symmetrical structure, creating an internal cavity.
The assembled protein cage has an external diameter of approximately 12 nanometers (nm) and an internal cavity ranging from 6 to 8 nm in diameter. Each polypeptide subunit folds into a specific shape, primarily consisting of a four-helix bundle with an additional C-terminal helix. This precise folding and arrangement of subunits enables the formation of the robust protein shell.
The Iron Core Within Ferritin
Inside the ferritin protein shell, iron is stored in a non-toxic, mineralized form. This mineral is specifically known as hydrated ferric oxide, or ferrihydrite. The internal cavity of a ferritin molecule has a remarkable capacity, capable of holding up to 4,500 iron atoms when fully saturated. However, the typical amount of iron stored is closer to about 2,000 atoms.
Storing iron in this inert, mineralized state prevents free iron from producing damaging reactive oxygen species and contributing to oxidative stress. The iron core within ferritin is not static; it is a dynamic reservoir that constantly undergoes processes of iron uptake and release as the cell’s needs change.
How Channels and Gates Regulate Iron Flow
Iron ions enter and exit the ferritin cage through specific channels or pores located within the protein shell. These channels serve as controlled entry and exit points for ferrous iron (Fe2+). There are typically eight hydrophilic channels in a 24-subunit ferritin, positioned at the three-fold symmetry axes of the protein cage.
These channels are narrow and selectively allow iron ions to pass, facilitating regulated movement of iron into and out of the internal cavity. The movement of ferrous ions through these gated pores is regulated by changes in the environment, which can cause the pores to “open” or “close,” thereby increasing or decreasing the rate of iron transport. This controlled transport mechanism is important for preventing the leakage of the stored iron core and maintaining cellular iron homeostasis.
Variations in Ferritin Subunits
Ferritin molecules are heteropolymers, meaning they are composed of varying ratios of two main types of subunits: H (heavy) and L (light) chains. These subunits, although structurally similar with about 55% sequence identity, possess distinct functional roles. The ratio of H to L subunits can vary depending on the specific tissue and physiological conditions; for instance, heart and brain ferritins often have a higher proportion of H subunits, while liver and spleen, major iron storage organs, contain more L subunits.
H-chains are characterized by their ferroxidase activity, which is performed at a dinuclear catalytic site within the subunit. This activity oxidizes ferrous iron (Fe2+) to ferric iron (Fe3+) using oxygen, a necessary step for iron storage and mineralization within the ferritin cavity. In contrast, L-chains lack this ferroxidase activity but have additional glutamate residues on their inner surface, which promote the nucleation and mineralization of the iron core. The specific combination of H and L subunits in a ferritin complex influences its overall function, including its iron uptake rate and stability.