An improved structural model of the human iron exporter ferroportin. Insight into the role of pathogenic mutations in hereditary hemochromatosis type 4

Ferroportin (Fpn) is a membrane protein representing the major cellular iron exporter, essential for metal translocation from cells into plasma. Despite its pivotal role in human iron homeostasis, many questions on Fpn structure and biology remain unanswered. In this work, we present two novel and more reliable structural models of human Fpn (hFpn; inward-facing and outwardfacing conformations) obtained using as templates the recently solved crystal structures of a bacterial homologue of hFpn, Bdellovibrio bacteriovorus Fpn. In the absence of an experimentally solved structure of hFpn, the structural predictions described here allow to analyze the role of pathogenic mutations in the Fpn-linked hereditary hemochromatosis disease and represent a valuable alternative for reliable structure-based functional studies on this human iron exporter.