The human iron exporter ferroportin. Insight into the transport mechanism by molecular modeling

Ferroportin (Fpn), a membrane protein belonging to the Major Facilitator Superfamily (MFS) of transporters, is the only vertebrate iron exporter known so far. Several Fpn mutations lead to the so-called ‘ferroportin disease’ or type 4 haemochromatosis, characterized by two distinct iron accumulation phenotypes depending on whether the mutation affects the activity of the protein or its degradation pathway. Through extensive molecular modelling analysis using the structures of all known MFS members as templates, we obtained multiple structural models of Fpn in the three mechanistically relevant conformations (inward-open, occluded and outward-open). The best models, selected on the ground of experimental data previously obtained on wild type and mutant Fpn, provide for the first time a prediction at the atomic level of the dynamics of the transporter. Based on these results, a possible mechanism for iron export is proposed.