RT Journal Article
SR Electronic
T1 Structural basis of ferroportin inhibition by minihepcidin PR73
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.23.505007
DO 10.1101/2022.08.23.505007
A1 Wilbon, Azaan Saalim
A1 Shen, Jiemin
A1 Ruchala, Piotr
A1 Zhou, Ming
A1 Pan, Yaping
YR 2022
UL http://biorxiv.org/content/early/2022/08/23/2022.08.23.505007.abstract
AB Ferroportin (Fpn) is the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small peptides that mimic the first few residues of hepcidin, i.e. minihepcidins, are more potent than hepcidin. However, the mechanism of enhanced inhibition by minihepcidins remains unclear. Here, we report the structure of human ferroportin in complex with a minihepcidin, PR73 that mimics the first 9 residues of hepcidin, at 2.7 Å overall resolution. The structure reveals novel interactions that were not present between Fpn and hepcidin. We validate PR73-Fpn interactions through binding and transport assays. These results provide insights into how minihepcidins increase inhibition potency and will guide future developments of Fpn inhibitors.Competing Interest StatementThe authors have declared no competing interest.