Skip to main content
SpringerLink
Log in
Book cover

Current Topics in Innate Immunity II pp 335–351Cite as

Nutritional Immunity: Homology Modeling of Nramp Metal Import

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 946))

Abstract

The Natural resistance-associated macrophage proteins (Nramp1 and 2) are proton-dependent solute carriers of divalent metals such as Fe2+ and Mn2+ (Slc11a1 and 2). Their expression in both resting and microbicidal macrophages which metabolize iron differently, raises questions about Nramp mechanism of Me2+ transport and its impact in distinct phenotypic contexts. We developed a low resolution 3D model for Slc11 based on detailed phylogeny and remote homology threading using Escherichia coli Nramp homolog (proton-dependent Mn 2+ transporter, MntH) as experimental system. The predicted fold is consistent with determinations of transmembrane topology and activity; it indicates Slc11 carriers are part of the LeuT superfamily. Homology implies that inverted structural symmetry facilitates Slc11 H+-driven Me2+ import and provides a 3D framework to test structure-activity relationships in macrophages and study functional evolution of MntH/Nramp (Slc11) carriers.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abramson J. and Wright E.M. (2009) Structure and function of Na(+)-symporters with inverted repeats. Curr Opin Struct Biol 19,425-32

    Article  PubMed  CAS  Google Scholar 

  • A-Gonzalez N., Bensinger S.J., Hong C., et al. (2009) Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31,245-58

    Article  PubMed  CAS  Google Scholar 

  • Anderson E.S., Paulley J.T., Gaines J.M., et al. (2009) The manganese transporter MntH is a critical virulence determinant for Brucella abortus 2308 in experimentally infected mice. Infect Immun 77,3466-74

    Article  PubMed  CAS  Google Scholar 

  • Bellora F., Castriconi R., Dondero A., et al. (2010) The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1007654108

    Google Scholar 

  • Bensinger S.J. and Tontonoz P. (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454,470-77

    Article  PubMed  CAS  Google Scholar 

  • Biswas S.K. and Mantovani A. (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11,889-96

    Article  PubMed  CAS  Google Scholar 

  • Blanco E., Kannengiesser C., Grandchamp B. et al. (2009) Not all DMT1 mutations lead to iron overload. Blood Cells Mol Dis 43,199-201

    Article  PubMed  CAS  Google Scholar 

  • Boudker O. and Verdon G. (2010) Structural perspectives on secondary active transporters. Trends Pharmacol Sci 31,418-26

    Article  PubMed  CAS  Google Scholar 

  • Brown S.A., Palmer K.L., Whiteley M. (2008) Revisiting the host as a growth medium. Nat Rev Microbiol 6,657-66

    Article  PubMed  CAS  Google Scholar 

  • Cailliatte R., Schikora A., Briat J.F., et al. (2010) High-affinity manganese uptake by the metal transporter NRAMP1 is essential for Arabidopsis growth in low manganese conditions. Plant Cell 22,904-17

    Article  PubMed  CAS  Google Scholar 

  • Cairo G., Locati M., Mantovani A. (2010) Control of iron homeostasis as a key component of macrophage polarization. Haematologica 95,1801-03

    Article  CAS  Google Scholar 

  • Cellier M., Privé G., Belouchi A., et al. (1995) Nramp defines a family of membrane proteins. Proc Natl Acad Sci U S A 92,10089-93

    Article  PubMed  CAS  Google Scholar 

  • Cellier M.F., Bergevin I., Boyer E., et al. (2001) Polyphyletic origins of bacterial Nramp transporters. Trends Genet 17,365-70

    Article  PubMed  CAS  Google Scholar 

  • Cellier M.F., Courville P., Campion C. (2007) Nramp1 phagocyte intracellular metal withdrawal defense. Microbes Infect 9,1662-70

    Article  PubMed  CAS  Google Scholar 

  • Chaloupka R., Courville P., Veyrier F., et al. (2005) Identification of functional amino acids in the Nramp family by a combination of evolutionary analysis and biophysical studies of metal and proton cotransport in vivo. Biochemistry 44,726-33

    Article  PubMed  CAS  Google Scholar 

  • Choi S., Jeon J., Yang J.S., et al. (2008) Common occurrence of internal repeat symmetry in membrane proteins. Proteins 71,68-80

    Article  PubMed  CAS  Google Scholar 

  • Claxton D.P., Quick M., Shi L., et al. (2010) Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters. Nat Struct Mol Biol 17,822-29

    Article  PubMed  CAS  Google Scholar 

  • Corna G., Campana L., Pignatti E., et al. (2010) Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 95,1814-22

    Article  PubMed  CAS  Google Scholar 

  • Courville P., Chaloupka R., Veyrier F., et al. (2004) Determination of transmembrane topology of the Escherichia coli natural resistance-associated macrophage protein (Nramp) ortholog. J Biol Chem 279,3318-26

    Article  PubMed  CAS  Google Scholar 

  • Courville P., Chaloupka R., Cellier M.F. (2006) Recent progress in structure-function analyses of Nramp proton-dependent metal-ion transporters. Biochem Cell Biol 84,960-78

    Article  PubMed  CAS  Google Scholar 

  • Courville P., Urbankova E., Rensing C., et al. (2008) Solute carrier 11 cation symport requires distinct residues in transmembrane helices 1 and 6. J Biol Chem 283,9651-58

    Article  PubMed  CAS  Google Scholar 

  • Czachorowski M., Lam-Yuk-Tseung S., Cellier M., et al. (2009) Transmembrane topology of the mammalian Slc11a2 iron transporter. Biochemistry 48,8422-34

    Article  PubMed  CAS  Google Scholar 

  • Dutzler R., Campbell E.B., Cadene M., et al. (2002) X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415,287-94

    Article  PubMed  CAS  Google Scholar 

  • Elkon K.B. (2009) Autoimmunity: apoptotic fats grease transcription. Nat Med 15,1246-48

    Article  PubMed  CAS  Google Scholar 

  • Elliott M.R. and Ravichandran K.S. (2010) Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189,1059-70

    Article  PubMed  CAS  Google Scholar 

  • Eswar N., Eramian D., Webb B., et al. (2008) Protein structure modeling with MODELLER. Methods Mol Biol 426,145-59

    Article  PubMed  CAS  Google Scholar 

  • Faham S., Watanabe A., Besserer G.M., et al. (2008) The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321,810-14

    Article  PubMed  CAS  Google Scholar 

  • Fang Y., Jayaram H., Shane T., et al. (2009) Structure of a prokaryotic virtual proton pump at 3.2 A resolution. Nature 460,1040-43

    PubMed  CAS  Google Scholar 

  • Fontaine C., Rigamonti E., Pourcet B., et al. (2008) The nuclear receptor Rev-erbalpha is a liver X receptor (LXR) target gene driving a negative feedback loop on select LXR-induced pathways in human macrophages. Mol Endocrinol 22,1797-811

    Article  PubMed  CAS  Google Scholar 

  • Forrest L.R. and Rudnick G. (2009) The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters. Physiology (Bethesda) 24,377-86

    Article  PubMed  CAS  Google Scholar 

  • Forrest L.R., Zhang Y.W., Jacobs M.T., et al. (2008) Mechanism for alternating access in neurotransmitter transporters. Proc Natl Acad Sci U S A 105,10338-43

    Article  PubMed  Google Scholar 

  • Fredriksson R., Nordstrom K.J., Stephansson O., et al. (2008) The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families. FEBS Lett 582,3811-16

    Article  PubMed  CAS  Google Scholar 

  • Frickey T. and Lupas A. (2004) CLANS: a Java application for visualizing protein families based on pairwise similarity. Bioinformatics 20,3702-04

    Article  PubMed  CAS  Google Scholar 

  • Ganz T. (2009) Iron in innate immunity: starve the invaders. Curr Opin Immunol 21,63-67

    Article  PubMed  CAS  Google Scholar 

  • Gao X., Zhou L., Jiao X., et al. (2010) Mechanism of substrate recognition and transport by an amino acid antiporter. Nature 463,828-32

    Article  PubMed  CAS  Google Scholar 

  • Geissmann F., Manz M.G., Jung S., et al. (2010) Development of monocytes, macrophages, and dendritic cells. Science 327,656-61

    Article  PubMed  CAS  Google Scholar 

  • Gordon S. and Martinez F.O. (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32,593-604

    Article  PubMed  CAS  Google Scholar 

  • Guda C., Lu S., Scheeff E.D., et al. (2004) CE-MC: a multiple protein structure alignment server. Nucleic Acids Res 32,W100-03

    Article  PubMed  CAS  Google Scholar 

  • Gunshin H., Fujiwara Y., Custodio A.O., et al. (2005) Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 115,1258-66

    PubMed  CAS  Google Scholar 

  • Howitt J., Putz U., Lackovic J., et al. (2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci U S A. 106,15489-94

    Article  PubMed  Google Scholar 

  • Jakubovics N.S. and Valentine R.A. (2009) A new direction for manganese homeostasis in bacteria: identification of a novel efflux system in Streptococcus pneumoniae. Mol Microbiol 72,1-4

    Article  PubMed  CAS  Google Scholar 

  • Javelle A., Lupo D., Ripoche P., et al. (2008) Substrate binding, deprotonation, and selectivity at the periplasmic entrance of the Escherichia coli ammonia channel AmtB. Proc Natl Acad Sci U S A. 105,5040-45

    Article  PubMed  Google Scholar 

  • Jeannin P., Jaillon S., Delneste Y. (2008) Pattern recognition receptors in the immune response against dying cells. Curr Opin Immunol 20,530-37

    Article  PubMed  CAS  Google Scholar 

  • Jensen L.T., Carroll M.C., Hall M.D. et al. (2009) Down-regulation of a manganese transporter in the face of metal toxicity. Mol Biol Cell 20,2810-19

    Article  PubMed  CAS  Google Scholar 

  • Kehl-Fie T.E. and Skaar E.P. (2010) Nutritional immunity beyond iron: a role for manganese and zinc. Curr Opin Chem Biol 14,218-24

    Article  PubMed  CAS  Google Scholar 

  • Khafizov K., Staritzbichler R., Stamm M., et al. (2010) A Study of the Evolution of Inverted-Topology Repeats from LeuT-Fold Transporters Using AlignMe. Biochemistry 49,10702-13

    Article  PubMed  CAS  Google Scholar 

  • Korkhov V.M. and Tate C.G. (2009) An emerging consensus for the structure of EmrE. Acta Crystallogr D Biol Crystallogr 65,186-92

    Article  PubMed  CAS  Google Scholar 

  • Krishnamurthy H., Piscitelli C.L., Gouaux E. (2009) Unlocking the molecular secrets of sodium-coupled transporters. Nature 459,347-55

    Article  PubMed  CAS  Google Scholar 

  • Kuntal B.K., Aparoy P., Reddanna P. (2010) EasyModeller: A graphical interface to MODELLER. BMC Res Notes 3,226

    Article  PubMed  CAS  Google Scholar 

  • Lam-Yuk-Tseung S. and Gros P. (2006) Distinct targeting and recycling properties of two isoforms of the iron transporter DMT1 (NRAMP2, Slc11A2). Biochemistry 45,2294-301

    Article  PubMed  CAS  Google Scholar 

  • Lam-Yuk-Tseung S., Picard V., Gros P. (2006) Identification of a tyrosine-based motif (YGSI) in the amino terminus of Nramp1 (Slc11a1) that is important for lysosomal targeting. J Biol Chem 281,31677-88

    Article  PubMed  CAS  Google Scholar 

  • Makui H., Roig E., Cole S.T., et al. (2000) Identification of the Escherichia coli K-12 Nramp orthologue (MntH) as a selective divalent metal ion transporter. Mol Microbiol 35,1065-78

    Article  PubMed  CAS  Google Scholar 

  • Marro S., Chiabrando D., Messana E., et al. (2010) Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica 95,1261-68

    Article  PubMed  CAS  Google Scholar 

  • Martinez F.O., Gordon S., Locati M., et al. (2006) Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 177,7303-11

    PubMed  CAS  Google Scholar 

  • Mukundan L., Odegaard J.I., Morel C.R., et al. (2009) PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15,1266-72

    Article  PubMed  CAS  Google Scholar 

  • Muñoz M., Villar I., García-Erce J.A. (2009) An update on iron physiology. World J Gastroenterol 15,4617-26

    Article  PubMed  CAS  Google Scholar 

  • Nasie I., Steiner-Mordoch S., Gold A., et al. (2010) Topologically random insertion of EmrE supports a pathway for evolution of inverted repeats in ion-coupled transporters. J Biol Chem 285,15234-44

    Article  PubMed  CAS  Google Scholar 

  • Odegaard J.I., Ricardo-Gonzalez R.R., Red Eagle A., et al. (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7,496-507

    Article  PubMed  CAS  Google Scholar 

  • Recalcati S., Locati M., Marini A., et al. (2010) Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 40,824-35

    Article  PubMed  CAS  Google Scholar 

  • Ressl S., Terwisscha van Scheltinga A.C., Vonrhein C., et al. (2009) Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP. Nature 458,47-52

    Article  PubMed  CAS  Google Scholar 

  • Richer E., Courville P., Bergevin I., et al. (2003) Horizontal gene transfer of “prototype” Nramp in bacteria. J Mol Evol 57,363-76

    Article  PubMed  CAS  Google Scholar 

  • Schmidt H.A. and von Haeseler A. (2007) Maximum-likelihood analysis using TREE-PUZZLE. Curr Protoc Bioinformatics Chapter 6:Unit 6.6

    Google Scholar 

  • Schug T.T. and Li X. (2009) PPARdelta-mediated macrophage activation: a matter of fat. Dis Model Mech 2,421-22

    Article  PubMed  CAS  Google Scholar 

  • Schulze S., Köster S., Geldmacher U., et al. (2010) Structural basis of Na(+)-independent and cooperative substrate/product antiport in CaiT. Nature 467,233-36

    Article  PubMed  CAS  Google Scholar 

  • Settivari R., Levora J., Nass R. (2009) The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in Caenorhabditis elegans models of manganism and parkinson disease. J Biol Chem 284,35758-68

    Article  PubMed  CAS  Google Scholar 

  • Shaffer P.L., Goehring A., Shankaranarayanan A., et al. (2009) Structure and mechanism of a Na+-independent amino acid transporter. Science 325,1010-14

    Article  PubMed  CAS  Google Scholar 

  • Shimamura T., Weyand S., Beckstein O., et al. (2010) Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1. Science 328,470-73

    Article  PubMed  CAS  Google Scholar 

  • Sierra-Filardi E., Vega M.A., Sánchez-Mateos P., et al. (2010) Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release. Immunobiology 215,788-95

    Article  PubMed  CAS  Google Scholar 

  • Soe-Lin S., Apte S.S., Andriopoulos B. Jr, et al. (2009) Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo. Proc Natl Acad Sci U S A 106,5960-65

    Article  PubMed  Google Scholar 

  • Takeuchi O. and Akira S. (2010) Pattern recognition receptors and inflammation. Cell 140,805-20

    Article  PubMed  CAS  Google Scholar 

  • Tamura K., Dudley J., Nei M., et al. (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24,1596-99

    Article  PubMed  CAS  Google Scholar 

  • Tang L., Bai L., Wang W.H., et al. (2010) Crystal structure of the carnitine transporter and insights into the antiport mechanism. Nat Struct Mol Biol 17,492-96

    Article  PubMed  CAS  Google Scholar 

  • Töröcsik D., Szanto A., Nagy L. (2009) Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages. Mol Aspects Med 30,134-52

    Article  PubMed  CAS  Google Scholar 

  • Vallelian F., Schaer C.A., Kaempfer T., et al. (2010) Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity. Blood 116,5347-56

    Article  PubMed  CAS  Google Scholar 

  • Vidal S.M., Malo D., Vogan K., et al. (1993) Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73,469-85

    Article  PubMed  CAS  Google Scholar 

  • Wang D., Song Y., Li J., et al. (2010) Structure and metal ion binding of the first transmembrane domain of DMT1. Biochim Biophys Acta doi:10.1016/j.bbamem.2010.11.005

    Google Scholar 

  • Weinberg E.D. (1977) Infection and iron metabolism. Am J Clin Nutr 30,1485-90

    PubMed  CAS  Google Scholar 

  • Weinberg E.D. (2009) Iron availability and infection. Biochim Biophys Acta 1790,600-05

    Article  PubMed  CAS  Google Scholar 

  • Weyand S., Shimamura T., Yajima S., et al. (2008) Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science 322,709-13

    Article  PubMed  CAS  Google Scholar 

  • Williams R.J. (2007) A system’s view of the evolution of life. J R Soc Interface 4,1049-70

    Article  PubMed  CAS  Google Scholar 

  • Xia J., Yamaji N., Kasai T., et al. (2010) Plasma membrane-localized transporter for aluminum in rice. Proc Natl Acad Sci U S A 107,18381-85

    Article  PubMed  Google Scholar 

  • Xiao S., Li J., Wang Y., et al. (2010) Identification of an “alpha-helix-extended segment-alpha-helix” conformation of the sixth transmembrane domain in DMT1. Biochim Biophys Acta 1798,1556-64

    Article  PubMed  CAS  Google Scholar 

  • Xiu Y.M. (1996) Trace elements in health and diseases. Biomed Environ Sci 9,130-36

    PubMed  CAS  Google Scholar 

  • Yamashita A., Singh S.K., Kawate T., et al. (2005) Crystal structure of a bacterial homologue of Na+/Cl–dependent neurotransmitter transporters. Nature 437,215-23

    Article  PubMed  CAS  Google Scholar 

  • Zhao Y., Quick M., Shi L., et al. (2010) Substrate-dependent proton antiport in neurotransmitter: sodium symporters. Nat Chem Biol 6,109-16

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I thank past and present lab members for their contribution to this work and Matthias Quick for his comments. This work was supported in part by the Fond pour la Recherche en Santé du Québec and the Canadian Institutes of Health Research.

Author information

Authors and Affiliations

  1. INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, 531, Bd des prairies, H7V 1B7, Laval, QC, Canada

    Mathieu F. M. Cellier

Authors
  1. Mathieu F. M. Cellier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mathieu F. M. Cellier .

Editor information

Editors and Affiliations

  1. Department Of Pathology Laboratory Of, Medicine, University Of Pennsylvania, Johnson Pavilion 410, Philadelphia, 19104, Pennsylvania, USA

    John D. Lambris

  2. Health Sciences Center, University of Louisville, Louisville, 40292, Kentucky, USA

    George Hajishengallis

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Cellier, M.F. (2012). Nutritional Immunity: Homology Modeling of Nramp Metal Import. In: Lambris, J., Hajishengallis, G. (eds) Current Topics in Innate Immunity II. Advances in Experimental Medicine and Biology, vol 946. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0106-3_19

Download citation

Publish with us

Policies and ethics

Search

Navigation