Structural Basis of Ferroportin Inhibition by Minihepcidin PR73

Authors

Azaan Saalim Wilbon
Jiemin Shen
Piotr Ruchala
Ming Zhou
Yaping Pan

Publication Date

1-1-2023

Journal

PLoS Biology

DOI

10.1371/journal.pbio.3001936

PMID

36649314

PMCID

PMC9882908

PubMedCentral® Posted Date

1-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Hepcidins, Hemochromatosis, Iron, Cation Transport Proteins

Abstract

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 development of Fpn inhibitors.

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