Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin

Taniguchi, Reiya; Kato, Hideaki E.; Font, Josep; Deshpande, C.N.; Wada, Miki; Ito, Koichi; Ishitani, Ryuichiro; Jormakka, Mika; Nureki, Osamu

doi:10.1038/ncomms9545

Cited by 110 publications

(173 citation statements)

References 53 publications

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“…Typically other transition metal ions have been used as a surrogate for iron in the biochemical investigation of iron transporters in vitro (32,33). Our results suggest that the difficulty with using iron in a minimal proteoliposome-based assay is due to the formation of nonspecific leaks in the vesicles presumably derived from lipid peroxidation.…”

Section: Discussionmentioning

confidence: 90%

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In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1

Christenson

Gallegos

Banerjee

2018

Journal of Biological Chemistry

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Mitoferrin-1 is a promiscuous transition metal transporterThe reactivity of iron is exploited across all kingdoms of life. The physiological roles that iron takes on are many-iron readily participates in redox reactions where it can donate or accept electrons, depending on its oxidation state. Iron plays essential roles in gas transport and sensing and can also act as a non-redox active metal ion cofactor in enzymes. Additionally, iron-containing cofactors can impart stability to folded proteins (1). Iron naturally occurs in the 2+ and the 3+ oxidation states but owing to the insolubility of Fe(III), the bioavailable form of iron is almost exclusively the 2+ form. The main route of cellular iron uptake is via the transferrin receptor pathway whereby transferrin-bound iron is targeted to endosomes and subsequently released from transferrin during endosomal acidification. Fe(II) is transported out of endosomes by divalent metal ion transporter (DMT1) and becomes available for incorporation into iron-containing proteins and cofactors (2).In eukaryotes, mitochondria are the hotspots for iron utilization-these organelles house heme assembly and the majority of Fe-S cluster biosynthesis apparatus (3,4). Mitochondria contain respiratory complexes which comprise many ironcontaining cofactors. Not surprisingly, http://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 90%

“…As depicted in Fig. 2 (32,33) and the use of Fe as a transporter substrate is quite scarce. We sought without success a robust reconstituted proteoliposomal Fe transport assay that worked reproducibly in our hands.…”

Section: Expressionmentioning

confidence: 99%

In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1

Christenson

Gallegos

Banerjee

2018

Journal of Biological Chemistry

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“…Upon binding to hepcidin, ferroportin is ubiquitinated on key lysine residues, endocytosed, and degraded in lysozomes, thereby inhibiting iron entry into the bloodstream. The crystal structure of a putative bacterial homologue of ferroportin was recently solved, which may yield important new insights into how ferroportin transports iron, and how hepcidin interacts with ferroportin to regulate its activity [6**]. Ferroportin also undergoes additional transcriptional and post-transcriptional regulation in a cell-type specific manner [5*].…”

Section: Hepcidin and Ferroportin Regulate Systemic Iron Balancementioning

confidence: 99%

Hepcidin regulation in the anemia of inflammation

Wang

Babitt²

2016

Current Opinion in Hematology

173

126

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Purpose of review Anemia is prevalent in patients with infections and other inflammatory conditions. Induction of the iron regulatory hormone hepcidin has been implicated in the pathogenesis of anemia of inflammation (AI). This review outlines recent discoveries in understanding how hepcidin and its receptor ferroportin are regulated, how they contribute to AI, and how this knowledge may help guide new diagnostic and therapeutic strategies for this disease. Recent findings IL6 is a primary driver for hepcidin induction in many models of AI, but the SMAD1/5/8 pathway also contributes, likely via Activin B and SMAD-STAT3 interactions at the hepcidin promoter. Hepcidin has an important functional role in many, but not all, forms of AI, although hepcidin-independent mechanisms also contribute. In certain populations, hepcidin assays may help target therapy with iron or erythropoiesis stimulating agents to patients who may benefit most. New therapies targeting the hepcidin-ferroportin axis have shown efficacy in pre-clinical and early clinical studies. Summary Recent studies confirm an important role for the hepcidin-ferroportin axis in the development of AI, but also highlight the diverse and complex pathogenesis of this disorder depending on the underlying disease. Hepcidin-based diagnostic and therapeutic strategies offer promise to improve anemia treatment, but more work is needed in this area.

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“…However, the putative metal-binding site in the iron exporter ferroportin contains a methionine (29), suggesting a strategy similar to Nramps' for selective transition metal transport. Underscoring the methionine's key metal selectivity role, a functionally diverged Nramp-related transporter of the hard metal Al 3+ in rice has a threonine (providing a hard oxygen ligand) in place of the methionine while retaining the other binding-site residues (30).…”

Section: Wtmentioning

confidence: 99%

Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters

Bozzi

Bane

Weihofen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

110

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Natural resistance-associated macrophage protein (Nramp) family transporters catalyze uptake of essential divalent transition metals like iron and manganese. To discriminate against abundant competitors, the Nramp metal-binding site should favor softer transition metals, which interact either covalently or ionically with coordinating molecules, over hard calcium and magnesium, which interact mainly ionically. The metal-binding site contains an unusual, but conserved, methionine, and its sulfur coordinates transition metal substrates, suggesting a vital role in their transport. Using a bacterial Nramp model system, we show that, surprisingly, this conserved methionine is dispensable for transport of the physiological manganese substrate and similar divalents iron and cobalt, with several small amino acid replacements still enabling robust uptake. Moreover, the methionine sulfur's presence makes the toxic metal cadmium a preferred substrate. However, a methionine-to-alanine substitution enables transport of calcium and magnesium. Thus, the putative evolutionary pressure to maintain the Nramp metal-binding methionine likely exists because it-more effectively than any other amino acid-increases selectivity for low-abundance transition metal transport in the presence of high-abundance divalents like calcium and magnesium.transition metals | MntH | divalent metal transporter DMT1 | hard-soft acid-base theory | ion selectivity filters A ll organisms require transition metal ions as cofactors in proteins that perform a variety of essential cellular tasks. Through evolution, organisms have developed mechanisms to acquire, transport, and safely store essential metals such as manganese, iron, cobalt, and zinc. The natural resistance-associated macrophage protein (Nramp) family of metal transporters represents a common transition metal acquisition strategy conserved across all kingdoms of life (1). The first discovered mammalian Nramp (Nramp1) is expressed in phagosomal membranes and likely extracts essential metals to help kill engulfed pathogens (2, 3). Mammals use Nramp2, an essential gene also called DMT1, to absorb dietary iron into the enterocytes that line the small intestine (4) and to extract iron from transferrin-containing endosomes in all tissues. Bacteria express their own Nramp homologs, which they typically use to scavenge manganese and other first row divalent transition metals (5, 6). Last, most plants have several Nramp homologs that take up iron and manganese, the essential cofactor in photosystem II, from the soil or vacuolar stores (7,8).Nramps are generally thought to function as metal-proton symporters (1) and are able to bind and/or transport a wide range of divalent transition metal substrates, including the biologically useful metals Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ , as well as the toxic heavy metals Cd 2+ , Pb 2+ , and Hg 2+ (4, 9-13). Nramps do discriminate against the divalent alkaline earth metal ions Mg 2+ and Ca 2+ (9, 14), which are typically several orders of magnitude mor...

show abstract

Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin

Cited by 110 publications

References 53 publications

In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1

In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1

Hepcidin regulation in the anemia of inflammation

Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters

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