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).
Ca2+ is required for human Fpn-mediated transport activity, and iron efflux is stimulated by extracellular Ca2+ in the physiological range, Ca2+, even though it is not transported. Deshpande et al. 2018 determined the crystal structure of a Ca2+-bound BbFpn, a prokaryotic orthologue (TC# 2.A.100.2.1), and found that Ca2+ is a cofactor that facilitates a conformational change critical to the transport cycle. They also identified a substrate pocket accommodating a divalent transition metal complexed with a chelator. These findings support a model of iron export by Fpn and suggest a link between plasma calcium and iron homeostasis (Deshpande et al. 2018).
The transport reaction catalyzed by Ferroportin is:
Fe2+ (in) + nH+ (out) ⇌ Fe2+ (out) + nH+ (in)