Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochem J
2001 Mar 15;354Pt 3:511-9. doi: 10.1042/0264-6021:3540511.
Show Gene links
Show Anatomy links
Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter.
Goswami T, Bhattacharjee A, Babal P, Searle S, Moore E, Li M, Blackwell JM.
???displayArticle.abstract???
In mammals, natural-resistance-associated macrophage protein 1 (Nramp1) regulates macrophage activation and is associated with infectious and autoimmune diseases. Nramp2 is associated with anaemia. Both belong to a highly conserved eukaryote/prokaryote protein family. We used Xenopus oocytes to demonstrate that, like Nramp2, Nramp1 is a bivalent cation (Fe2+, Zn2+ and Mn2+) transporter. Strikingly, however, where Nramp2 is a symporter of H+ and metal ions, Nramp1 is a highly pH-dependent antiporter that fluxes metal ions in either direction against a proton gradient. At pH 9.0, oocytes injected with cRNA from wild-type murine Nramp1 with a glycine residue at position 169 (Nramp1(G169); P=3.22x10(-6)) and human NRAMP1 (P=3.87x10(-5)) showed significantly enhanced uptake of radiolabelled Zn2+ compared with water-injected controls. At pH 5.5, Nramp1(G169) (P=1.34x10(-13)) and NRAMP1 (P=1.09x10(-6)) oocytes showed significant efflux of Zn2+. Zn2+ transport was abolished when the proton gradient was dissipated using carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Using pre-acidified oocytes, currents of 130+/-57 nA were evoked by 100 microM Zn2+ at pH 7.5, and 139+/-47 nA by 100 microM Fe2+ at pH 7.0, in Nramp1(G169) oocytes; currents of 254+/-49 nA and 242+/-26 nA were evoked, respectively, in NRAMP1 oocytes. Steady-state currents evoked by increasing concentrations of Zn2+ were saturable, with apparent affinity constants of approx. 614 nM for Nramp1(G169) and approx. 562 nM for NRAMP1 oocytes, and a curvilinear voltage dependence of transporter activity (i.e. the data points approximate to a curve that approaches a linear asymptote). In the present study we propose a new model for metal ion homoeostasis in macrophages. Under normal physiological conditions, Nramp2, localized to early endosomal membranes, delivers extracellularly acquired bivalent cations into the cytosol. Nramp1, localized to late endosomal/lysosomal membranes, delivers bivalent cations from the cytosol into this acidic compartment where they may directly affect antimicrobial activity.
Aballay,
Zn2+ depletion blocks endosome fusion.
1995,
Pubmed Abel,
Susceptibility to leprosy is linked to the human NRAMP1 gene.
1998,
Pubmed Atkinson,
Ectopic expression of Nramp1 in COS-1 cells modulates iron accumulation.
1998,
Pubmed Barton,
Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways.
1995,
Pubmed Bellamy,
Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.
1998,
Pubmed Blackwell,
Genetic regulation of macrophage activation: understanding the function of Nramp1 (=Ity/Lsh/Bcg).
1999,
Pubmed Blackwell,
Understanding the multiple functions of Nramp1.
2000,
Pubmed Brown,
Stabilized expression of mRNA is associated with mycobacterial resistance controlled by Nramp1.
1997,
Pubmed Canonne-Hergaux,
Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron.
1999,
Pubmed Cellier,
Resistance to intracellular infections: comparative genomic analysis of Nramp.
1996,
Pubmed de Chastellier,
Implication of phagosome-lysosome fusion in restriction of Mycobacterium avium growth in bone marrow macrophages from genetically resistant mice.
1993,
Pubmed Fleming,
Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.
1997,
Pubmed Fleming,
Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport.
1998,
Pubmed Fritz,
Quantitative photometrical assessment of iron deposits in synovial membranes in different joint diseases.
1996,
Pubmed Garner,
Endogenous ferritin protects cells with iron-laden lysosomes against oxidative stress.
1998,
Pubmed Gerlach,
Altered brain metabolism of iron as a cause of neurodegenerative diseases?
1994,
Pubmed Gomes,
Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium.
1998,
Pubmed Goswitz,
Structural features of the uniporter/symporter/antiporter superfamily.
1995,
Pubmed Griffith,
Membrane transport proteins: implications of sequence comparisons.
1992,
Pubmed Gruenheid,
Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome.
1997,
Pubmed Gruenheid,
The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes.
1999,
Pubmed Gunshin,
Cloning and characterization of a mammalian proton-coupled metal-ion transporter.
1997,
Pubmed
,
Xenbase Hackam,
Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification.
1998,
Pubmed Hirsch,
Iron metabolism and Parkinson's disease.
1998,
Pubmed Hofmeister,
The natural resistance-associated macrophage protein gene is associated with Crohn's disease.
1997,
Pubmed Hughes,
Protein phylogenies provide evidence of a radical discontinuity between arthropod and vertebrate immune systems.
1998,
Pubmed Jabado,
Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane.
2000,
Pubmed Jellinger,
Iron and ferritin in substantia nigra in Parkinson's disease.
1993,
Pubmed Krantz,
Pathogenesis and treatment of the anemia of chronic disease.
1994,
Pubmed Kuhn,
Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169.
1999,
Pubmed Lang,
Nramp1 transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on antigen processing and presentation.
1997,
Pubmed Lee,
The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms.
1998,
Pubmed Liu,
Mutational analysis of Saccharomyces cerevisiae Smf1p, a member of the Nramp family of metal transporters.
1999,
Pubmed Liu,
Post-translation control of Nramp metal transport in yeast. Role of metal ions and the BSD2 gene.
1999,
Pubmed Marger,
A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport.
1993,
Pubmed Multhaup,
Amyloid precursor protein, copper and Alzheimer's disease.
1997,
Pubmed Nelson,
Metal ion transporters and homeostasis.
1999,
Pubmed Nelson,
Energizing porters by proton-motive force.
1994,
Pubmed Orgad,
Metal ions suppress the abnormal taste behavior of the Drosophila mutant malvolio.
1998,
Pubmed Picard,
Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool.
2000,
Pubmed Pinner,
Functional complementation of the yeast divalent cation transporter family SMF by NRAMP2, a member of the mammalian natural resistance-associated macrophage protein family.
1997,
Pubmed Rodrigues,
malvolio, the Drosophila homologue of mouse NRAMP-1 (Bcg), is expressed in macrophages and in the nervous system and is required for normal taste behaviour.
1995,
Pubmed Sanjeevi,
Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis.
2000,
Pubmed Searle,
Localisation of Nramp1 in macrophages: modulation with activation and infection.
1998,
Pubmed Shaw,
Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35.
1996,
Pubmed Supek,
A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria.
1996,
Pubmed Varela,
Nucleotide and deduced protein sequences of the class D tetracycline resistance determinant: relationship to other antimicrobial transport proteins.
1993,
Pubmed Vidal,
Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg.
1993,
Pubmed Wall,
Isolation of plasma membrane complexes from Xenopus oocytes.
1989,
Pubmed
,
Xenbase Yip,
The roles of inflammation and iron deficiency as causes of anemia.
1988,
Pubmed Yuan,
Effects of iron- and hemoglobin-loaded human monocyte-derived macrophages on oxidation and uptake of LDL.
1995,
Pubmed Yuan,
Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis.
1996,
Pubmed Zwilling,
Role of iron in Nramp1-mediated inhibition of mycobacterial growth.
1999,
Pubmed
