Figure 7. Mapping of functionally important residues on the hFPN homology model.

(a) Mapping of disease-related mutation sites on the hFPN homology model. The residues involved in the intracellular gate interactions and the hepcidin binding are coloured orange and blue, respectively. Other mutation sites are coloured green. In the middle panel, TM helices are represented as semitransparent cylinders, and the Cα atoms of the mutation sites are indicated by CPK spheres. The surface representation of the N lobe, viewed from the inside of the central cavity, is shown in the left panel, while that of the C lobe is shown in the right panel. (b) Mapping of the hepcidin-binding residues on the hFPN homology model. The side chains of these residues are represented by CPK models. In the right panel, the N lobe is omitted for clarity. (c) Possible model of the hepcidin-mediated inhibition of hFPN. Hepcidin, represented as the yellow oval, binds to the hFPN C lobe, inhibiting its state transition toward the inward-facing state. Hepcidin binding may also change the conformation of the intracellular side of hFPN, which triggers the ubiquitination and subsequent internalization.