Hepcidin binds to a highly conserved domain on an extracellular loop of ferroportin.8 Binding of hepcidin results in recruitment of JAK2 to a not-yet-characterized intracellular domain. JAK2 phosphorylates tyrosines at positions 302 and 303. This phosphorylation event is required for internalization of ferroportin. Once internalized, lysine at position 253 is ubiquitinated, targeting the protein for lysosomal degradation. Ferroportin functions as a homodimer and binding of hepcidin to both monomers is required to initiate internalization.
