| Structural highlights
Disease
S40A1_HUMAN SLC40A1-related hemochromatosis;Ferroportin disease. The disease is caused by variants affecting the gene represented in this entry.
Function
S40A1_HUMAN Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis (PubMed:15692071, PubMed:22178646, PubMed:22682227, PubMed:24304836, PubMed:29237594, PubMed:29599243, PubMed:30247984). Transports iron from intestinal, splenic, hepatic cells, macrophages and erythrocytes into the blood to provide iron to other tissues (By similarity). Controls therefore dietary iron uptake, iron recycling by macrophages and erythrocytes, and release of iron stores in hepatocytes (By similarity). When iron is in excess in serum, circulating HAMP/hepcidin levels increase resulting in a degradation of SLC40A1, thus limiting the iron efflux to plasma (PubMed:22682227, PubMed:29237594, PubMed:32814342).[UniProtKB:Q9JHI9][1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe(2+)) from cells and is important for homeostasis of iron in circulation. Export of one Fe(2+) by Fpn is coupled to import of two H(+) to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca(2+) transport. We determine the structure of Ca(2+)-bound HsFpn and identify a single Ca(2+) binding site distinct from the Fe(2+) binding sites. Further studies validate the Ca(2+) binding site and show that Ca(2+) transport is not coupled to transport of another ion. In addition, Ca(2+) transport is significantly inhibited in the presence of Fe(2+) but not vice versa. Function of Fpn as a Ca(2+) uniporter may allow regulation of iron homeostasis by Ca(2+).
Mechanism of Ca(2+) transport by ferroportin.,Shen J, Wilbon AS, Zhou M, Pan Y Elife. 2023 Jan 17;12:e82947. doi: 10.7554/eLife.82947. PMID:36648329[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood. 2005 May 15;105(10):4096-102. doi: 10.1182/blood-2004-11-4502. Epub 2005 , Feb 3. PMID:15692071 doi:http://dx.doi.org/10.1182/blood-2004-11-4502
- ↑ Madejczyk MS, Ballatori N. The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta. 2012 Mar;1818(3):651-7. PMID:22178646 doi:10.1016/j.bbamem.2011.12.002
- ↑ Qiao B, Sugianto P, Fung E, Del-Castillo-Rueda A, Moran-Jimenez MJ, Ganz T, Nemeth E. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab. 2012 Jun 6;15(6):918-24. doi: 10.1016/j.cmet.2012.03.018. PMID:22682227 doi:http://dx.doi.org/10.1016/j.cmet.2012.03.018
- ↑ Mitchell CJ, Shawki A, Ganz T, Nemeth E, Mackenzie B. Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc. Am J Physiol Cell Physiol. 2014 Mar 1;306(5):C450-9. PMID:24304836 doi:10.1152/ajpcell.00348.2013
- ↑ Aschemeyer S, Qiao B, Stefanova D, Valore EV, Sek AC, Ruwe TA, Vieth KR, Jung G, Casu C, Rivella S, Jormakka M, Mackenzie B, Ganz T, Nemeth E. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood. 2018 Feb 22;131(8):899-910. doi: 10.1182/blood-2017-05-786590. Epub 2017 , Dec 13. PMID:29237594 doi:http://dx.doi.org/10.1182/blood-2017-05-786590
- ↑ Zhang DL, Wu J, Shah BN, Greutélaers KC, Ghosh MC, Ollivierre H, Su XZ, Thuma PE, Bedu-Addo G, Mockenhaupt FP, Gordeuk VR, Rouault TA. Erythrocytic ferroportin reduces intracellular iron accumulation, hemolysis, and malaria risk. Science. 2018 Mar 30;359(6383):1520-1523. PMID:29599243 doi:10.1126/science.aal2022
- ↑ Choi EK, Nguyen TT, Iwase S, Seo YA. Ferroportin disease mutations influence manganese accumulation and cytotoxicity. FASEB J. 2019 Feb;33(2):2228-2240. PMID:30247984 doi:10.1096/fj.201800831R
- ↑ Billesbolle CB, Azumaya CM, Kretsch RC, Powers AS, Gonen S, Schneider S, Arvedson T, Dror RO, Cheng Y, Manglik A. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature. 2020 Aug 19. pii: 10.1038/s41586-020-2668-z. doi:, 10.1038/s41586-020-2668-z. PMID:32814342 doi:http://dx.doi.org/10.1038/s41586-020-2668-z
- ↑ Shen J, Wilbon AS, Zhou M, Pan Y. Mechanism of Ca(2+) transport by ferroportin. Elife. 2023 Jan 17;12:e82947. doi: 10.7554/eLife.82947. PMID:36648329 doi:http://dx.doi.org/10.7554/eLife.82947
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