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Human Ferroportin Mediates Proton-Coupled Active Transport of Iron

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Human Ferroportin Mediates Proton-Coupled Active Transport of Iron Washington University School of Medicine Digital Commons@Becker Open Access Publications 2020 Human ferroportin mediates proton-coupled active transport of iron Shuang Li Yihu Yang Weikai Li Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs REGULAR ARTICLE Human ferroportin mediates proton-coupled active transport of iron Shuang Li,* Yihu Yang,* and Weikai Li Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/19/4758/1760209/advancesadv2020001864.pdf by WASHINGTON UNIVERSITY SCHOOL user on 27 October 2020 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO As the sole iron exporter in humans, ferroportin controls systemic iron homeostasis through Key Points exporting iron into the blood plasma. The molecular mechanism of how ferroportin exports • Active iron export by iron under various physiological settings remains unclear. Here we found that purified 1 ferroportin can be ferroportin incorporated into liposomes preferentially transports Fe2 and exhibits lower driven by proton affinities of transporting other divalent metal ions. The iron transport by ferroportin is gradient and charge facilitated by downhill proton gradients at the same direction. Human ferroportin is also potential. capable of transporting protons, and this activity is tightly coupled to the iron transport. • Mutagenesis analysis Remarkably, ferroportin can conduct active transport uphill against the iron gradient, with suggests that the iron favorable charge potential providing the driving force. Targeted mutagenesis suggests that translocation site is at the iron translocation site is located at the pore region of human ferroportin. Together, our the pore region of studies enhance the mechanistic understanding by which human ferroportin transports ferroportin. iron and suggest that a combination of electrochemical gradients regulates iron export. Introduction Ferroportin is the only iron exporter known in vertebrates.1 At the systemic level, ferroportin exports iron into the blood plasma from most cells involved in iron metabolism,2 including dietary iron absorbed by duodenal enterocytes,3 stored iron released from hepatocytes,4 and the majority of body iron that is recycled by macrophages through erythropoiesis. During pregnancy, ferroportin releases maternal iron from placenta syncytiotrophoblasts into the fetal circulation.5 In addition to handling systemic iron flow, ferroportin maintains local iron balance in heart and other tissues.6,7 Ferroportin has been proposed to act as a “safety valve” that relieves cardiomyocytes8 from iron-overload conditions such as those caused by thalassemia treatment.9-12 An important regulator of ferroportin is hepcidin,13-15 a peptide hormone triggering the internalization and subsequent degradation of the iron exporter. This regulation represents the most important control point of systemic iron homeostasis.2,8 Despite the physiological importance of ferroportin, the molecular mechanism of iron export remains unclear. Ferroportin belongs to the major facilitator superfamily (MFS) of membrane transporters, most of which use a cotransport mechanism, with proton being the typical coupling ion.16-19 The coupling enables the proton cotransporters to overcome an unfavorable substrate gradient that can occur under certain physiological conditions. The cotransport activity of ferroportin, however, is not obvious from previous studies conducted in Xenopus oocytes,20,21 of which the intracellular pH cannot be controlled. In addition, it is difficult to analyze metal efflux from cells20 because metal ions injected into the cells can be sequestered by small chelator molecules or chaperone proteins. The cellular studies20,21 show that 1 1 1 1 ferroportin can transport Fe2 ,Co2 , and Zn2 but disagree on whether ferroportin can transport Cd2 1 and Mn2 . To resolve these difficulties, the current study determined the transport activity of purified human 1 ferroportin in liposomes. Purified ferroportin actively transports Fe2 as in cells. Other divalent metal 1 1 1 ions, Co2 ,Ni2 , and Mn2 , are transported with decreasing affinities. Ferroportin can transport 1 1 protons, and this activity requires the cotransport of Fe2 (or Co2 ). Moreover, ferroportin can conduct Submitted 16 March 2020; accepted 27 August 2020; published online 2 October Requests for data sharing may be submitted to the corresponding author (Weikai Li; 2020. DOI 10.1182/bloodadvances.2020001864. e-mail: [email protected]). The full-text version of this article contains a data supplement. *S.L. and Y.Y. contributed equally to this study. © 2020 by The American Society of Hematology 4758 13 OCTOBER 2020 x VOLUME 4, NUMBER 19 1 1 uphill active transport against a Fe2 (or Co2 ) gradient. Mutagen- Transport assay of divalent metal ions esis analyses suggest that the iron translocation site is at the pore The reconstitution buffer used for the metal transport assay region of ferroportin. Elucidation of the transport mechanism of contained 150 mM NaCl and 25 mM of different pH buffers, which human ferroportin has implications for the control of iron export under are MES-NaOH pH 6.0, MES-NaOH pH 6.5, HEPES-NaOH pH various physiological settings. 7.0, HEPES-NaOH pH 7.5, and Tris-HCl pH 8.0. These pH buffers Methods and the buffers containing 5 mM CaCl2 were used during the lipid resuspension and ferroportin reconstitution. After the reconstitution, Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/19/4758/1760209/advancesadv2020001864.pdf by WASHINGTON UNIVERSITY SCHOOL user on 27 October 2020 Cloning and protein purification the proteoliposomes were mixed 1:1 (vol/vol) with the reconstitution m The coding sequence of human ferroportin was amplified with buffers containing 500 M calcein. Calcein was enclosed into the polymerase chain reaction from an untagged clone (OriGene proteoliposomes through 3 freeze-thaw cycles and sonication. The SC127301) and subcloned into a modified pPICZ-B expression proteoliposomes were subsequently passed through a G50 desalting vector (supplemental Figure 1A). A PreScission protease cleavage column to remove free calcein and to exchange the buffers outside of site, enhanced green fluorescent protein sequence, and 103 the liposomes. histidine tag were added to the C-terminal of ferroportin. Ferroportin The metal transport assay was performed in 96-well plates with mutants were generated by site-directed mutagenesis with the use a Synergy 2 plate reader (BioTek), and the calcein fluorescence of QuikChange. The nucleotide sequences of all the constructs was detected with the excitation wavelength at 494 nm and were verified by DNA sequencing. emission at 516 nm. After 5 minutes equilibration, 10 mM FeCl2, m m m Wild-type and mutant ferroportin constructs were linearized and 100 M CoCl2, 100 M MnCl2, or 100 M NiCl2 was added. For m transformed into Pichia pastoris. Zeocin-resistant colonies with the the competition assay, 100 M of ZnCl2, CdCl2, CaCl2, or MgCl2 m highest expression level were inoculated to BMG media (1% glycerol, was added together with 10 M FeCl2. The metal transport through 0.34% yeast nitrogen base, 1% ammonium sulfate, 0.4 mg/mL biotin, ferroportin was monitored for another 20 minutes. At 25 minutes, and 100 mM potassium phosphate, pH 6.0) and grown at 30°C for 1 mM calcimycin was added to allow metal influx through this 20 hours. After an exchange to the media without glycerol, protein ionophore. The intensity of the calcein fluorescence at 25 minutes expression was induced with 0.7% methanol for 2 days at 25°C. The was expressed as a percentage of the fluorescence before the cells were harvested by centrifugation and flash-frozen in liquid metal ions were added (between 0 and 5 minutes), and this was nitrogen. used as a measure of transport activity. For protein purification, 20 g frozen Pichia cells were applied to Proton transport assay a ball mill (Retsch) to break the cell wall. The cell membrane was subsequently solubilized in a buffer containing 2% n-dodecyl The proteoliposomes were enclosed with a reconstitution buffer containing 150 mM KCl and 25 mM HEPES-KOH pH 7.5. b-D-maltoside (DDM), 300 mM NaCl, 100 mM Tris-HCl, pH 8.0, 10 mg/mL DNase I, and protease inhibitors. After centrifugation, the Subsequently, the proteoliposomes were flowed through a G50 supernatant was incubated with Ni-NTA agarose, and the resin was column prewashed with 150 mM NaCl and 25 mM HEPES pH 7.5. m subsequently washed in a buffer containing 20 mM imidazole, For the analysis of proton uptake, the same buffer with 1 M9- 50 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 0.2% DDM. amino-6-chloro-2-methoxyacridine (ACMA) was added at the outside of the liposome; ACMA can diffuse freely into the liposomes PreScission protease was added to remove the enhanced green 22 fluorescent protein and 103 histidine tag from ferroportin. After the but cannot diffuse out once it is proton bound. The ACMA in-resin digestion, the protein was collected and concentrated for fluorescence was detected with an excitation wavelength at 410 nm m the subsequent purification by size-exclusion chromatography and emission at 490 nm. After 5 minutes of equilibration, 10 M m (Superdex 200). The peak fractions showing the highest UV FeCl2 (or 20 M CoCl2) and 20 nM valinomycin were added to absorbance (supplemental Figure 1A) were pooled and concen- generate an electrochemical gradient. The proton transport through trated to 20 mg/mL, and the fresh protein was immediately used for ferroportin was monitored for another 20 minutes. At 25 minutes, m liposome reconstitution. 1 M carbonyl cyanide m-chlorophenyl hydrazone (CCCP) was added to allow proton influx through this proton channel. The Reconstitution of ferroportin into liposomes intensity of the ACMA fluorescence at 25 minutes was expressed as a percentage of the fluorescence before the metal ions were The lipid mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoe- added (between 0 and 5 minutes), and this was used as a measure thanolamine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1’- of proton transport activity.
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