The Ferroxidase-Permease System for Transport of Iron Across Membranes: From Yeast to Humans

Abstract

Transport of iron across the cell membrane is a tightly controlled process carried out by specific proteins in all living cells. In yeast and in mammals, a system formed by an enzyme with ferroxidase activity coupled to a membrane transporter supports iron uptake or iron efflux, respectively. Ferroxidase belongs to the family of blue multicopper oxidases, enzymes able to couple the one-electron oxidation of substrate(s) to full reduction of molecular oxygen to water. On the other hand, the permeases are widely different and are specific to Fe³⁺ and Fe²⁺ in yeast and multicellular organisms, respectively. This review will describe the yeast and human ferroxidase-permease systems, highlighting similarities and differences in structure, function and regulation of the respective protein components.

Keywords: Fet3; Ftr1; ceruloplasmin; copper; ferroportin; ferroxidase; hephaestin; iron; multicopper oxidase; yeast.

Figure 1

The yeast and human ferroxidase–permease system. Fpn: ferroportin; Cp: ceruloplasmin; Heph: hephaestin.

Figure 2

Fe binding site in Fet3 (PDB ID 1ZPU). The 3D structure of the protein is shown (a), together with a close-up view of the Fe-binding site (b). The T1 Cu atom is colored blue, the TNC is in cyan. Residues E185, D283 and D409 are colored in red, green and magenta, respectively. T1 Cu ligands and the His-Cys-His T1 Cu-TNC branched pathway are highlighted.

Figure 3

Fe binding sites in domains 4 and 6 of Cp (PDB ID 2J5W). The 3D structure of the protein is shown (a), together with a close-up view of the metal-binding sites (b). The T1 Cu atoms are colored blue, the TNC is cyan with dioxygen in orange. The metal atom in the Fe-binding site in domain 6 is in red, side chains involved in Fe binding are highlighted, together with the His-Cys-His T1 Cu-TNC branched pathway.

Figure 4

AlphaFold model of S. cerevisiae Ftr1 (Uniprot ID: P40088) with acidic residues of REXLE, E89 and DASE motifs evidenced in red, magenta and cyan respectively (a). Negatively charged surface patch on the extracellular side of Ftr1 (b).

Figure 5

Schematic representation of the three-dimensional structure of human Fpn in complex with Co²⁺ (PDB ID 8Dl8). The first and second repeat of the N-domain are in orange and light blue, respectively. The corresponding repeats of the C-domain are in red and blue. The large intracellular region connecting the two domains is in gray. Metal binding residues are shown in stick representation, and the cobalt ions are shown as pink spheres.