Structural Basis of Ion Transport and Inhibition in Ferroportin

Authors

Yaping Pan
Zhenning Ren
Shuai Gao
Jiemin Shen
Lie Wang
Zhichun Xu
Ye Yu
Preetham Bachina
Hanzhi Zhang
Xiao Fan
Arthur Laganowsky
Nieng Yan
Ming Zhou

Publication Date

11-10-2020

Journal

Nature Communications

DOI

10.1038/s41467-020-19458-6

PMID

33173040

PMCID

PMC7655804

PubMedCentral® Posted Date

11-10-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Anemia, Iron-Deficiency, Animals, Binding Sites, Cation Transport Proteins, Cryoelectron Microscopy, Hepcidins, Humans, Ion Transport, Iron, Protein Binding

Abstract

Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H+/Fe2+ antiporter so that transport of each Fe2+ is coupled to transport of two H+ in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H+ and Fe2+. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases.

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