期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms9545
关键词
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资金
- Platform for Drug Discovery, Informatics and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Japan Society for the Promotion of Science (JSPS) through its 'Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program)'
- Core Research for Evolutional Science and Technology (CREST) Program 'The Creation of Basic Medical Technologies to Clarify and Control the Mechanisms Underlying Chronic Inflammation' of the Japan Science and Technology Agency (JST)
- MEXT [24227004, 25291011]
- National Health and Medical Research Council [APP1035693, APP1083536]
- X-ray Free Electron Laser Priority Strategy Program (MEXT)
- National Breast Cancer Foundation
- National Breast Cancer Foundation [PF-12-04] Funding Source: researchfish
In vertebrates, the iron exporter ferroportin releases Fe2+ from cells into plasma, thereby maintaining iron homeostasis. The transport activity of ferroportin is suppressed by the peptide hormone hepcidin, which exhibits upregulated expression in chronic inflammation, causing iron-restrictive anaemia. However, due to the lack of structural information about ferroportin, the mechanisms of its iron transport and hepcidin-mediated regulation remain largely elusive. Here we report the crystal structures of a putative bacterial homologue of ferroportin, BbFPN, in both the outward- and inward-facing states. Despite undetectable sequence similarity, BbFPN adopts the major facilitator superfamily fold. A comparison of the two structures reveals that BbFPN undergoes an intra-domain conformational rearrangement during the transport cycle. We identify a substrate metal-binding site, based on structural and mutational analyses. Furthermore, the BbFPN structures suggest that a predicted hepcidin-binding site of ferroportin is located within its central cavity. Thus, BbFPN may be a valuable structural model for iron homeostasis regulation by ferroportin.
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