Structure of human ferroportin (SLC40A1) inferred from mass spectrometry restraints

Abstract

Abstract Nearly all organisms require iron for red blood cell manufacture, respiration, metabolism and immunity, and as cofactor in several enzymes. Paradoxically, free iron is toxic from the production of reactive oxygen species which induce cellular injury and damage to DNA. It is essential that iron is tightly regulated. Ferroportin is the only known exporter of cellular iron in mammals. Its function and expression are tightly regulated by hepcidin. Carriers of ferroportin mutation Q248H show reduced sensitivity to hepcidin, have elevated iron stores and high HIV-1 viral load. In HIV-1 infection, there is marked alteration in iron balance indicated by high ferritin levels. As well, iron-regulating peptide hepcidin is greatly elevated. High iron stores correlate with high morbidity, increased opportunistic infections and faster progression to AIDS: high iron content in bone marrow macrophage parallels greater infection, immune dysfunction and poor prognosis. By contrast, other studies show that patients who were being treated for iron overload with iron chelators had delayed AIDS progression and longer survival. In spite of its importance little structural information is available on human ferroportin, and how iron is transported through ferroportin is not understood. We have built the structure of ferroportin using hybrid methods with restraints from mass spectrometry. Our model comprises 12 transmembrane helices. The iron binding site matches what is seen in crystal structures of distant orthologs. We are using this structure along with functional data to answer outstanding questions about the mechanism of ferroportin, iron transport and the importance of the Q248H mutation found in African and black American populations.