Iron Transport

Many proteins depend on iron as a co-factor for redox reactions or ligand coordination. The facile conversion between ferrous (Fe²⁺) and ferric iron (Fe³⁺) poses significant dangers to living cells, however, as it can lead to the formation of hydroxyl radicals, a major source for oxidative damage to proteins, nucleic acids and lipids. Moreover, under physiological conditions ferric iron forms a highly insoluble hydroxide complex, so that despite its abundance, iron is not easily accessible to cells. Toxicity and insolubility have forced the evolution of highly sophisticated machineries for acquiring, storing, and distributing iron.

Cells acquire iron by the internalization of transferrin (Tf) with the transferrin receptor (TfR). Transferrin-independent transport by DMT1 and SFT also can be detected. The low endosomal pH results in the release of Fe³⁺ from the TfR-Tf complex. Reduction of iron is required for the endosomal transport of iron; however, transport-associated ferrireductases have not been identified. Iron enters an intermediate pool that is sensed by IRP1 and IRP2. Iron regulation of IRPs results in increased ferritin translation, leading to iron sequestration, and destabilization of TfR mRNA.

We are working on the structure determination of a number of proteins involved in iron transport. For integral membrane proteins we attempt to grow 2D crystals and to solve their structure by electron crystallography. For proteins that are merely anchored to the membrane by a transmembrane α-helix, e.g. the transferrin receptor, we express the proteins without the membrane anchor and visualize their structure by single particle electron microscopy.

TfR-Tf Complex