Hypothetical model showing how hepcidin regulates the activity of the iron exporter ferroportin.⁴  Intracellular Fe²⁺ ions approach and bind to a site buried in the N-lobe of Fpn in its inward-facing state, which converts the Fpn conformation to an outward-facing state that permits export of iron. Apo-Fpn then reverts to the inward-facing state to transport another intracellular iron ion. When hepcidin levels are high, hepcidin binds and occludes the central cavity, which prevents the conformational transition and iron export. When hepcidin levels decrease under iron deficiency, hepcidin does not occupy the central cavity, which enables Fpn to resume iron export. Hepcidin binding also triggers a conformational change that exposes several ubiquitination sites, and the ubiquitination initiates the internalization and degradation of Fpn.