| 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 the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small peptides that mimic the first few residues of hepcidin, i.e., minihepcidins, are more potent than hepcidin. However, the mechanism of enhanced inhibition by minihepcidins remains unclear. Here, we report the structure of human ferroportin in complex with a minihepcidin, PR73 that mimics the first 9 residues of hepcidin, at 2.7 A overall resolution. The structure reveals novel interactions that were not present between Fpn and hepcidin. We validate PR73-Fpn interactions through binding and transport assays. These results provide insights into how minihepcidins increase inhibition potency and will guide future development of Fpn inhibitors.
Structural basis of ferroportin inhibition by minihepcidin PR73.,Wilbon AS, Shen J, Ruchala P, Zhou M, Pan Y PLoS Biol. 2023 Jan 17;21(1):e3001936. doi: 10.1371/journal.pbio.3001936. , eCollection 2023 Jan. PMID:36649314[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:https://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:https://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:https://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:https://dx.doi.org/10.1038/s41586-020-2668-z
- ↑ Wilbon AS, Shen J, Ruchala P, Zhou M, Pan Y. Structural basis of ferroportin inhibition by minihepcidin PR73. PLoS Biol. 2023 Jan 17;21(1):e3001936. PMID:36649314 doi:10.1371/journal.pbio.3001936
|
