Structural basis of ion transport and inhibition in ferroportin

Yaping Pan (), Zhenning Ren, Shuai Gao (), Jiemin Shen, Lie Wang, Zhichun Xu, Ye Yu, Preetham Bachina, Hanzhi Zhang, Xiao Fan, Arthur Laganowsky, Nieng Yan and Ming Zhou ()
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Yaping Pan: Baylor College of Medicine
Zhenning Ren: Baylor College of Medicine
Shuai Gao: Princeton University
Jiemin Shen: Baylor College of Medicine
Lie Wang: Baylor College of Medicine
Zhichun Xu: Baylor College of Medicine
Ye Yu: Baylor College of Medicine
Preetham Bachina: Baylor College of Medicine
Hanzhi Zhang: Baylor College of Medicine
Xiao Fan: Princeton University
Arthur Laganowsky: Texas A & M University
Nieng Yan: Princeton University
Ming Zhou: Baylor College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19458-6

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