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-Structure paper
タイトル | Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. |
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ジャーナル・号・ページ | Nature, Vol. 586, Issue 7831, Page 807-811, Year 2020 |
掲載日 | 2020年8月19日 |
著者 | Christian B Billesbølle / Caleigh M Azumaya / Rachael C Kretsch / Alexander S Powers / Shane Gonen / Simon Schneider / Tara Arvedson / Ron O Dror / Yifan Cheng / Aashish Manglik / |
PubMed 要旨 | The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing ...The serum level of iron in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin regulates iron absorption and recycling by inducing the internalization and degradation of ferroportin. Aberrant ferroportin activity can lead to diseases of iron overload, such as haemochromatosis, or iron limitation anaemias. Here we determine cryogenic electron microscopy structures of ferroportin in lipid nanodiscs, both in the apo state and in complex with hepcidin and the iron mimetic cobalt. These structures and accompanying molecular dynamics simulations identify two 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 to inhibit transport. The carboxy terminus of hepcidin directly contacts the divalent metal in the ferroportin C domain. 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 model for hepcidin regulation of ferroportin, in which only ferroportin molecules loaded with iron are targeted for degradation. More broadly, our structural and functional insights may enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis. |
リンク | Nature / PubMed:32814342 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.1 - 3.2 Å |
構造データ | EMDB-21539, PDB-6w4s: EMDB-21599, PDB-6wbv: PDB-6w4v: |
化合物 | ChemComp-EDO: ChemComp-HOH: ChemComp-AGA: ChemComp-CO: |
由来 |
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キーワード | TRANSPORT PROTEIN/IMMUNE SYSTEM / ferroportin (フェロポーチン) / transporter (運搬体タンパク質) / iron (鉄) / hepcidin / TRANSPORT PROTEIN-IMMUNE SYSTEM complex / IMMUNE SYSTEM (免疫系) / antibody (抗体) / Fab / TRANSLOCASE/IMMUNE SYSTEM/HORMONE / TRANSLOCASE-IMMUNE SYSTEM-HORMONE complex |