Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin

Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1182/blood-2017-05-786590
Journal or Publication Title: Blood
Volume: 131
Number: 8
Page Range: pp. 899-910
Date: 2018
Divisions: Structural Biology
Depositing User: General Admin
Identification Number: 10.1182/blood-2017-05-786590
ISSN: 0006-4971
Date Deposited: 03 Jan 2021 22:23
Abstract:

Nonclassical ferroportin disease (FD) is a form of hereditary hemochromatosis caused by mutations in the iron transporter ferroportin (Fpn), resulting in parenchymal iron overload. Fpn is regulated by the hormone hepcidin, which induces Fpn endocytosis and cellular iron retention. We characterized 11 clinically relevant and 5 nonclinical Fpn mutations using stably transfected, inducible isogenic cell lines. All clinical mutants were functionally resistant to hepcidin as a consequence of either impaired hepcidin binding or impaired hepcidin-dependent ubiquitination despite intact hepcidin binding. Mapping the residues onto 2 computational models of the human Fpn structure indicated that (1) mutations that caused ubiquitination-resistance were positioned at helix-helix interfaces, likely preventing the hepcidin-induced conformational change, (2) hepcidin binding occurred within the central cavity of Fpn, (3) hepcidin interacted with up to 4 helices, and (4) hepcidin binding should occlude Fpn and interfere with iron export independently of endocytosis. We experimentally confirmed hepcidin-mediated occlusion of Fpn in the absence of endocytosis in multiple cellular systems: HEK293 cells expressing an endocytosis-defective Fpn mutant (K8R), Xenopus oocytes expressing wild-type or K8R Fpn, and mature human red blood cells. We conclude that nonclassical FD is caused by Fpn mutations that decrease hepcidin binding or hinder conformational changes required for ubiquitination and endocytosis of Fpn. The newly documented ability of hepcidin and its agonists to occlude iron transport may facilitate the development of broadly effective treatments for hereditary iron overload disorders.

© 2018 by The American Society of Hematology.

Creators:
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Aschemeyer, Sharraya
UNSPECIFIED
Qiao, Bo
UNSPECIFIED
Stefanova, Deborah
UNSPECIFIED
Valore, Erika V.
UNSPECIFIED
Sek, Albert C.
UNSPECIFIED
Ruwe, T. Alex
UNSPECIFIED
Vieth, Kyle R.
UNSPECIFIED
Jung, Grace
UNSPECIFIED
Casu, Carla
UNSPECIFIED
Rivella, Stefano
UNSPECIFIED
Jormakka, Mika
UNSPECIFIED
Mackenzie, Bryan
UNSPECIFIED
Ganz, Tomas
UNSPECIFIED
Nemeth, Elizabeta
UNSPECIFIED
Last Modified: 03 Jan 2021 22:23
URI: https://eprints.centenary.org.au/id/eprint/562

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