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2.A.100 The Ferroportin (Fpn) Family

The Ferroportin Family is called the FPN1 family in Pfam.  Ferroportin 1, also called IREG1 (or MTP1 (Slc11a3) (570 aas) is an iron-regulated transporter that is found in the basolateral membranes of intestinal epithilia and in phagocytic cells of the reticuloendothelial system of mammals (Delaby et al., 2007). The protein catalyzes exit of divalent metal ions from the epithelial cell into the tissues. Orthologues in the mouse and humans have been characterized. Homologues are found in a variety of plants and animals. These proteins are of between 400 and 800 aas and exhibit 8-11 putative TMSs. IREG1 appears to have 10 TMSs based on hydropathy plots. Because ferroportin extrudes Fe2+ from the cell which has a membrane potential negative inside, ferroportin is presumed to function by cation (H+ or Na+) antiport. Studies with antisera to different epitopes of ferroportin (Fpn) indicated that it has 11 TMSs, with the C-terminus exposed on the cell surface (Yeh et al., 2011). 

Ferroportin is proposed to function in intestinal iron absorption as follows: (1) Fe3+ is reduced to Fe2+ by a ferric reductase localized to the apical membrane. (2) Fe2+ crosses the brush boarder membrane via the proton-coupled divalent cation transporter, DCT1. (3) Fe2+ is exported across the basolateral membrane via IREG1. (4) A copper oxidase, hephaestin, converts Fe2+ to Fe3+ in preparation for binding by circulating transferrin. The liver-secreted peptide hormone, Hepcidin, binds to ferroportin, promoting internalization and degradation (Chen and Enns, 2011). Ferroportin can also function as a manganese exporter (Madejczyk and Ballatori, 2011). Reduced interactions between ferroportin and Heph aestin after iron ingestion indicated that dissociation is a regulatory mechanism for limiting further iron absorption (Yeh et al., 2011).

Ferroportin-1 is associated with excess iron deposits in human macrophages. It plays an essential role in iron recycling from erythrophagocytosed red cells. Its expression is regulated by increasing cytoplasmic iron or copper (Chung et al., 2004). Its expression after erythrophagocytosis in mouse macrophages is induced early by heme, followed by iron-mediated, post-transcriptional regulation of the exporter (Delaby et al., 2007). The distribution of DMT1 and ferroportin (FPN) in the apical versus basolateral membranes has been studied as a function of iron supply with surprising observations (Núñez et al., 2010).

There are two closely related paralogs of mammalian ferroportin (FPN) in Arabidopsis thaliana, IRON REGULATED1 (IREG1/FPN1) and IREG2/FPN2 (Morrissey et al., 2009). FPN1 localizes to the plasma membrane and is expressed in the stele, suggesting a role in vascular loading; FPN2 localizes to the vacuole and is expressed in the two outermost layers of the root in response to iron deficiency, suggesting a role in buffering metal influx. Consistent with these roles, fpn2 has a diminished iron deficiency response, whereas fpn1 fpn2 has an elevated iron deficiency response. Ferroportins also play a role in cobalt homeostasis; a survey of Arabidopsis accessions for ionomic phenotypes showed that truncation of FPN2 results in elevated shoot cobalt levels and leads to increased sensitivity to the metal. Conversely, loss of FPN1 abolishes shoot cobalt accumulation, even in the cobalt accumulating mutant frd3. Consequently, in the fpn1 fpn2 double mutant, cobalt cannot move to the shoot via FPN1 and is not sequestered in the root vacuoles via FPN2; instead, cobalt likely accumulates in the root cytoplasm causing fpn1 fpn2 to be even more sensitive to cobalt than fpn2 mutants. (Morrissey et al., 2009).

The transport reaction catalyzed by Ferroportin is:

Fe2+ (in) + nH+ (out) ⇌ Fe2+ (out) + nH+ (in)

This family belongs to the: MFS Superfamily.

References associated with 2.A.100 family:

Anderson, G.J., D.M. Frazer, A.T. McKie, S.J. Wilkins, and C.D. Vulpe. (2002). The expression and regulation of the iron transport molecules hephaestin and IREG1: implications for the control of iron export from the small intestine. Cell Biochem. Biophys. 36: 137-146. 12139399
Chen J. and Enns CA. (2012). Hereditary hemochromatosis and transferrin receptor 2. Biochim Biophys Acta. 1820(3):256-63. 21864651
Chen, H., T. Su, Z.K. Attieh, T.C. Fox, A.T. McKie, G.J. Anderson, and C.D. Vulpe. (2003). Systemic regulation of HEPHAESTIN and IREG1 revealed in studies of genetic and nutritional iron deficiency. Blood 102: 1893-1899. 12730111
Chung, J., D.J. Haile, and M. Wessling-Resnick. (2004). Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux. Proc. Natl. Acad. Sci. USA 101: 2700-2705. 14973193
Cioffi, A.G., J. Hou, A.S. Grillo, K.A. Diaz, and M.D. Burke. (2015). Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel. J. Am. Chem. Soc. 137: 10096-10099. 26230309
Conte, S., D. Stevenson, I. Furner, and A. Lloyd. (2009). Multiple antibiotic resistance in Arabidopsis is conferred by mutations in a chloroplast-localized transport protein. Plant Physiol. 151: 559-573. 19675150
Delaby, C., N. Pilard, H. Puy, and F. Canonne-Hergaux (2008). Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. Biochem J 411: 123-31. 18072938
Grillo, A.S., A.M. SantaMaria, M.D. Kafina, A.G. Cioffi, N.C. Huston, M. Han, Y.A. Seo, Y.Y. Yien, C. Nardone, A.V. Menon, J. Fan, D.C. Svoboda, J.B. Anderson, J.D. Hong, B.G. Nicolau, K. Subedi, A.A. Gewirth, M. Wessling-Resnick, J. Kim, B.H. Paw, and M.D. Burke. (2017). Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals. Science 356: 608-616. 28495746
Le Gac G., Ka C., Joubrel R., Gourlaouen I., Lehn P., Mornon JP., Ferec C. and Callebaut I. (2013). Structure-function analysis of the human ferroportin iron exporter (SLC40A1): effect of hemochromatosis type 4 disease mutations and identification of critical residues. Hum Mutat. 34(10):1371-80. 23784628
Madejczyk, M.S. and N. Ballatori. (2012). The iron transporter ferroportin can also function as a manganese exporter. Biochim. Biophys. Acta. 1818: 651-657. 22178646
McKie, A.T. and D.J. Barlow. (2004). The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch. 447: 801-806. 12836025
McKie, A.T., P. Marciani, A. Rolfs, K. Brennan, K. Wehr, D. Barrow, S. Miret, A. Bomford, T.J. Peters, F. Farzaneh, M.A. Hediger, M.W. Hentze, and R. J. Simpson. (2000). A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell. 5: 299-309. 10882071
Morrissey, J., I.R. Baxter, J. Lee, L. Li, B. Lahner, N. Grotz, J. Kaplan, D.E. Salt, and M.L. Guerinot. (2009). The ferroportin metal efflux proteins function in iron and cobalt homeostasis in Arabidopsis. Plant Cell 21: 3326-3338. 19861554
Núñez, M.T., V. Tapia, A. Rojas, P. Aguirre, F. Gómez, and F. Nualart. (2010). Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1. Am. J. Physiol. Cell Physiol. 298: C477-485. 20007457
Taniguchi, R., H.E. Kato, J. Font, C.N. Deshpande, M. Wada, K. Ito, R. Ishitani, M. Jormakka, and O. Nureki. (2015). Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat Commun 6: 8545. 26461048
Yang, F., X. Liu, M. Quinones, P.C. Melby, A. Ghio, and D.J. Haile. (2002). Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J. Biol. Chem. 277: 39786-39791. 12161425
Yeh, K.Y., M. Yeh, and J. Glass. (2011). Interactions between ferroportin and hephaestin in rat enterocytes are reduced after iron ingestion. Gastroenterology 141: 292-9, 299.e1. 21473866