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Structure of human ferroportin bound to hepcidin and cobalt in lipid nanodisc
Structural highlights
DiseaseHEPC_HUMAN Defects in HAMP are the cause of hemochromatosis type 2B (HFE2B) [MIM:613313; also known as juvenile hemochromatosis (JH). HFE2B is a disorder of iron metabolism with excess deposition of iron in the tissues, bronze skin pigmentation, hepatic cirrhosis, arthropathy and diabetes. The most common symptoms of hemochromatosis type 2 at presentation are hypogonadism and cardiomyopathy.[1] [2] [3] [4] [5] FunctionHEPC_HUMAN Seems to act as a signaling molecule involved in the maintenance of iron homeostasis. Seems to be required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages (By similarity).[6] Has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker against S.epidermidis, S.aureus and group b streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.[7] Publication Abstract from PubMedThe serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing ferroportin internalization and degradation(1). Aberrant ferroportin activity can lead to diseases of iron overload, such as hemochromatosis, or iron limitation anemias(2). Here, we determined cryogenic electron microscopy (cryo-EM) structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with cobalt, an iron mimetic, and hepcidin. These structures and accompanying molecular dynamics simulations identify two metal binding sites within the N- and C-domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway to inhibit transport. The carboxy-terminus of hepcidin directly contacts the divalent metal in the ferroportin C-domain. We further show that hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms.,Billesbolle CB, Azumaya CM, Kretsch RC, Powers AS, Gonen S, Schneider S, Arvedson T, Dror RO, Cheng Y, Manglik A Nature. 2020 Aug 19. pii: 10.1038/s41586-020-2668-z. doi:, 10.1038/s41586-020-2668-z. PMID:32814342[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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