Structure of human ferroportin bound to hepcidin reveals mechanisms of iron homeostasis
Christian B. Billesbølle,
Caleigh M. Azumaya,
Rachael C. Kretsch,
Alexander S Powers,
Ron O. Dror,
Posted 18 Mar 2020
bioRxiv DOI: 10.1101/2020.03.16.993006
Posted 18 Mar 2020
The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin negatively regulates iron absorption and recycling by inducing ferroportin internalization and degradation. Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron limitation anemias. Here, we determined cryogenic electron microscopy (cryo-EM) structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with cobalt, an iron mimetic, and hepcidin. These structures and accompanying molecular dynamics simulations identify two divalent metal binding sites within the N- and C-domains of ferroportin. Hepcidin binds ferroportin in an outward-open conformation and completely occludes the iron efflux pathway. The carboxy-terminus of hepcidin directly contacts the divalent metal in the FPN C-domain. We further show that hepcidin binding to ferroportin is coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. These results suggest a new model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis. ### Competing Interest Statement Tara Arvedson is employed by Amgen and reports Amgen stock. None of the other authors report conflicts of interest.
- Downloaded 1,362 times
- Download rankings, all-time:
- Site-wide: 8,050 out of 101,046
- In biochemistry: 196 out of 3,448
- Year to date:
- Site-wide: 1,632 out of 101,046
- Since beginning of last month:
- Site-wide: 6,041 out of 101,046
Downloads over time
Distribution of downloads per paper, site-wide
- 20 Oct 2020: Support for sorting preprints using Twitter activity has been removed, at least temporarily, until a new source of social media activity data becomes available.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!