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Neutrophil Gelatinase-associated Lipocalin, a Siderophore-binding Eukaryotic Protein

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Abstract

NGAL (neutrophil gelatinase-associated lipocalin) also known as lcn2 or siderochalin is constitutively expressed in myelocytes and stored in specific granules of neutrophils. It is highly induced in a variety of epithelial cells during inflammation. Analysis of the crystal structure of NGAL expressed in E.coli showed that NGAL has the ability to bind catecholate type siderophores and in this way prevent bacteria from acquisition of siderophore-bound iron. NGAL (or 24p3 as the highly homologous murine orthologue is named) knock out mice have a profound defect in defense against E.coli after intraperitoneal injection. This defect can be mimicked in wild-type mice by providing siderophore iron, which cannot be sequestered by NGAL, testifying to the specific role of NGAL as a siderophore binding protein in innate immunity. Megalin, a scavenger receptor functions as a receptor for NGAL and mediates uptake into endosomes, but other NGAL receptors are likely to exist.

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References

  • JF Andersen A Weichsel CA Balfour DE Champagne WR Montfort (1998) ArticleTitleThe crystal structure of nitrophorin 4 at 1.5 angstrom resolution: transport of nitric oxide by a lipocalin-based heme protein Structure 6 1315–1327 Occurrence Handle9782054 Occurrence Handle1:CAS:528:DyaK1cXnt1Ogu78%3D Occurrence Handle10.1016/S0969-2126(98)00131-2

    Article  PubMed  CAS  Google Scholar 

  • RJ Beynon JL Hurst (2003) ArticleTitleMultiple roles of major urinary proteins in the house mouse, Mus domesticus Biochem Soc Trans 31 142–146 Occurrence Handle12546672 Occurrence Handle1:CAS:528:DC%2BD3sXptF2ltw%3D%3D Occurrence Handle10.1042/BST0310142

    Article  PubMed  CAS  Google Scholar 

  • N Borregaard JB Cowland (1997) ArticleTitleGranules of the human neutrophilic polymorphonuclear leukocyte Blood 89 3503–3521 Occurrence Handle9160655 Occurrence Handle1:CAS:528:DyaK2sXjt12nsrc%3D

    PubMed  CAS  Google Scholar 

  • L Briand D Trotier JC Pernollet (2004) ArticleTitleAphrodisin, an aphrodisiac lipocalin secreted in hamster vaginal secretions Peptides 25 1545–1552 Occurrence Handle15374656 Occurrence Handle1:CAS:528:DC%2BD2cXnslGnsLg%3D Occurrence Handle10.1016/j.peptides.2003.10.026

    Article  PubMed  CAS  Google Scholar 

  • JR Bundgaard N Borregaard L Kjeldsen (1994) ArticleTitleMolecular cloning and expression of a cDNA encoding NGAL: a lipocalin expressed in human neutrophils Biochem Biophys Res Commun 202 1468–1475 Occurrence Handle8060329 Occurrence Handle1:CAS:528:DyaK2MXkt1Gnsg%3D%3D Occurrence Handle10.1006/bbrc.1994.2096

    Article  PubMed  CAS  Google Scholar 

  • F Canonne-Hergaux J Calafat E Richer et al. (2002) ArticleTitleExpression and subcellular localization of NRAMP1 in human neutrophil granules Blood 100 268–275 Occurrence Handle12070036 Occurrence Handle1:CAS:528:DC%2BD38XltF2rtr0%3D Occurrence Handle10.1182/blood.V100.1.268

    Article  PubMed  CAS  Google Scholar 

  • M Cianci PJ Rizkallah A Olczak et al. (2002) ArticleTitleThe molecular basis of the coloration mechanism in lobster shell: beta-crustacyanin at 3.2-A resolution Proc Natl Acad Sci USA 99 9795–9800 Occurrence Handle12119396 Occurrence Handle1:CAS:528:DC%2BD38XlslKgs7o%3D Occurrence Handle10.1073/pnas.152088999

    Article  PubMed  CAS  Google Scholar 

  • SW Cowan ME Newcomer TA Jones (1990) ArticleTitleCrystallographic refinement of human serum retinol binding protein at 2 Å resolution Proteins: Struct Function Genet 8 44–61 Occurrence Handle1:CAS:528:DyaK3cXlsVOmsrc%3D Occurrence Handle10.1002/prot.340080108

    Article  CAS  Google Scholar 

  • JB Cowland N Borregaard (1997) ArticleTitleMolecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans Genomics 45 17–23 Occurrence Handle9339356 Occurrence Handle1:CAS:528:DyaK2sXmslejs7g%3D Occurrence Handle10.1006/geno.1997.4896

    Article  PubMed  CAS  Google Scholar 

  • JB Cowland OE Sorensen M Sehested N Borregaard (2003) ArticleTitleNeutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1beta, but not by TNF-alpha J Immunol 171 6630–6639 Occurrence Handle14662866 Occurrence Handle1:CAS:528:DC%2BD3sXpsV2rt70%3D

    PubMed  CAS  Google Scholar 

  • LR Devireddy JG Teodoro FA Richard MR Green (2001) ArticleTitleInduction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation Science 293 829–834 Occurrence Handle11486081 Occurrence Handle1:CAS:528:DC%2BD3MXlvVKksLs%3D Occurrence Handle10.1126/science.1061075

    Article  PubMed  CAS  Google Scholar 

  • TH Flo KD Smith S Sato et al. (2004) ArticleTitleLipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron Nature 432 917–921 Occurrence Handle15531878 Occurrence Handle1:CAS:528:DC%2BD2cXhtVOht7rE Occurrence Handle10.1038/nature03104

    Article  PubMed  CAS  Google Scholar 

  • DR. Flower (1996) ArticleTitleThe lipocalin protein family: structure and function Biochem J 318 1–14 Occurrence Handle8761444 Occurrence Handle1:CAS:528:DyaK28XltlKrtLc%3D

    PubMed  CAS  Google Scholar 

  • M Fluckinger H Haas P Merschak BJ Glasgow B Redl (2004) ArticleTitleHuman tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores Antimicrob Agents Chemother 48 3367–3372 Occurrence Handle15328098 Occurrence Handle1:CAS:528:DC%2BD2cXnsVehsro%3D Occurrence Handle10.1128/AAC.48.9.3367-3372.2004

    Article  PubMed  CAS  Google Scholar 

  • P FuentesPrior C NoeskeJungblut P Donner WD Schleuning R Huber W Bode (1997) ArticleTitleStructure of the thrombin complex with triabin, a lipocalin-like exosite-binding inhibitor derived from a triatomine bug Proc Natl Acad Sci USA 94 11845–11850 Occurrence Handle1:CAS:528:DyaK2sXntFSmsrw%3D Occurrence Handle10.1073/pnas.94.22.11845

    Article  CAS  Google Scholar 

  • MD Ganfornina G Gutierrez M Bastiani D Sanchez (2000) ArticleTitleA phylogenetic analysis of the lipocalin protein family Mol Biol Evol 17 114–126 Occurrence Handle10666711 Occurrence Handle1:CAS:528:DC%2BD3cXot1SjsQ%3D%3D

    PubMed  CAS  Google Scholar 

  • DH Goetz MA Holmes N Borregaard ME Bluhm KN Raymond RK Strong (2002) ArticleTitleThe neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition Mol Cell 10 1033–1043 Occurrence Handle12453412 Occurrence Handle1:CAS:528:DC%2BD38Xptl2ksLk%3D Occurrence Handle10.1016/S1097-2765(02)00708-6

    Article  PubMed  CAS  Google Scholar 

  • DH Goetz ST Willie RS Armen T Bratt N Borregaard RK Strong (2000) ArticleTitleLigand preference inferred from the structure of neutrophil gelatinase-associated lipocalin Biochemistry 39 1935–1941 Occurrence Handle10684642 Occurrence Handle1:CAS:528:DC%2BD3cXns1emsw%3D%3D Occurrence Handle10.1021/bi992215v

    Article  PubMed  CAS  Google Scholar 

  • MA Holmes W Paulsene X Jide C Ratledge RK Strong (2005) ArticleTitleSiderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration Structure (Camb) 13 29–41 Occurrence Handle1:CAS:528:DC%2BD2MXitVehtQ%3D%3D Occurrence Handle10.1016/j.str.2004.10.009

    Article  CAS  Google Scholar 

  • V Hvidberg C Jacobsen RK Strong JB Cowland SK Moestrup N Borregaard (2005) ArticleTitleThe endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake FEBS Lett 579 773–777 Occurrence Handle15670845 Occurrence Handle1:CAS:528:DC%2BD2MXmsVGrtw%3D%3D Occurrence Handle10.1016/j.febslet.2004.12.031

    Article  PubMed  CAS  Google Scholar 

  • L Kjeldsen DF Bainton H Sengeløv N Borregaard (1994) ArticleTitleIdentification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils Blood 83 799–807 Occurrence Handle8298140 Occurrence Handle1:CAS:528:DyaK2cXhvVyjs78%3D

    PubMed  CAS  Google Scholar 

  • L Kjeldsen AH Johnsen H Sengeløv N Borregaard (1993) ArticleTitleIsolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase J Biol Chem 268 10425–10432 Occurrence Handle7683678 Occurrence Handle1:CAS:528:DyaK2cXpvFKqsA%3D%3D

    PubMed  CAS  Google Scholar 

  • V Kopecky SuffixJr R Ettrich K Hofbauerova V Baumruk (2003) ArticleTitleStructure of human alpha-1 acid glycoprotein and its high-affinity binding site Biochem Biophys Res Commun 300 41–46 Occurrence Handle12480518 Occurrence Handle1:CAS:528:DC%2BD38Xps1Whu7c%3D Occurrence Handle10.1016/S0006-291X(02)02765-1

    Article  PubMed  CAS  Google Scholar 

  • V Le Cabec J Calafat N Borregaard (1997) ArticleTitleSorting of the specific granule protein, NGAL during granulocytic maturation of HL-60 cells Blood 89 2113–2121 Occurrence Handle9058734 Occurrence Handle1:CAS:528:DyaK2sXhvVars7k%3D

    PubMed  CAS  Google Scholar 

  • V Le Cabec JB Cowland J Calafat N Borregaard (1996) ArticleTitleTargeting of proteins to granule subsets determined by timing not by sorting: the specific granule protein NGAL is localized to azurophil granules when expressed in HL-60 cells Proc Natl Acad Sci USA 93 6454–6457 Occurrence Handle8692836 Occurrence Handle1:CAS:528:DyaK28XjvFejurs%3D Occurrence Handle10.1073/pnas.93.13.6454

    Article  PubMed  CAS  Google Scholar 

  • L Logdberg L Wester (2000) ArticleTitleImmunocalins: a lipocalin subfamily that modulates immune and inflammatory responses Biochim Biophy Acta 1482 284–297 Occurrence Handle1:CAS:528:DC%2BD3MXotFKi

    CAS  Google Scholar 

  • O Loreal C Haziza-Pigeon MB Troadec et al. (2005) ArticleTitleHepcidin in iron metabolism Curr Protein Pept Sci 6 279–291 Occurrence Handle15974953 Occurrence Handle1:CAS:528:DC%2BD2MXkvF2qur0%3D Occurrence Handle10.2174/1389203054065392

    Article  PubMed  CAS  Google Scholar 

  • S Marchese D Pes A Scaloni V Carbone P Pelosi (1998) ArticleTitleLipocalins of boar salivary glands binding odours and pheromones Eur J Biochem 252 563–568 Occurrence Handle9546674 Occurrence Handle1:CAS:528:DyaK1cXitVWntLg%3D Occurrence Handle10.1046/j.1432-1327.1998.2520563.x

    Article  PubMed  CAS  Google Scholar 

  • SK Moestrup PJ Verroust (2001) ArticleTitleMegalin- and cubilin-mediated endocytosis of protein-bound vitamins, lipids, and hormones in polarized epithelia Annu Rev Nutr 21 407–428 Occurrence Handle11375443 Occurrence Handle1:CAS:528:DC%2BD3MXlvFyku7c%3D Occurrence Handle10.1146/annurev.nutr.21.1.407

    Article  PubMed  CAS  Google Scholar 

  • WR Montfort A Weichsel JF Andersen (2000) ArticleTitleNitrophorins and related antihemostatic lipocalins from Rhodnius prolixus and other blood-sucking arthropods Biochim Biophys Acta 1482 110–118 Occurrence Handle11058753 Occurrence Handle1:CAS:528:DC%2BD3MXotFCm

    PubMed  CAS  Google Scholar 

  • JB Neilands (1995) ArticleTitleSiderophores: structure and function of microbial iron transport compounds J Biol Chem 270 26723–26726 Occurrence Handle7592901 Occurrence Handle1:CAS:528:DyaK2MXpsVGmurw%3D

    PubMed  CAS  Google Scholar 

  • ME Newcomer DE Ong (2000) ArticleTitlePlasma retinol binding protein: structure and function of the prototypic lipocalin Biochim Biophys Acta 1482 57–64 Occurrence Handle11058747 Occurrence Handle1:CAS:528:DC%2BD3MXotFeq

    PubMed  CAS  Google Scholar 

  • BS Nielsen N Borregaard JR Bundgaard S Timshel M Sehested L Kjeldsen (1996) ArticleTitleInduction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel disease Gut 38 414–420 Occurrence Handle8675096 Occurrence Handle1:STN:280:BymB2cnptlw%3D

    PubMed  CAS  Google Scholar 

  • OE Sorensen JB Cowland K Theilgaard-Monch L Liu T Ganz N Borregaard (2003) ArticleTitleWound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors J Immunol 170 5583–5589 Occurrence Handle12759437 Occurrence Handle1:CAS:528:DC%2BD3sXjvVyntbo%3D

    PubMed  CAS  Google Scholar 

  • RK Strong T Bratt JB Cowland N Borregaard FC Wiberg AJ Ewald (1998) ArticleTitleExpression, purification, crystallization and crystallographic characterization of dimeric and monomeric human neutrophil gelatinase associated lipocalin (NGAL) Acta Crystallogr D Biol Crystallogr 54 IssueIDPt 1 93–95 Occurrence Handle9761822 Occurrence Handle1:STN:280:DyaK1cvjslCruw%3D%3D Occurrence Handle10.1107/S0907444997010615

    Article  PubMed  CAS  Google Scholar 

  • M Vijay-Kumar JR Gentsch WJ Kaiser et al. (2005) ArticleTitleProtein kinase R mediates intestinal epithelial gene remodeling in response to double-stranded RNA and live rotavirus J Immunol 174 6322–6331 Occurrence Handle15879132 Occurrence Handle1:CAS:528:DC%2BD2MXjvV2mtbY%3D

    PubMed  CAS  Google Scholar 

  • J Yang D Goetz JY Li et al. (2002) ArticleTitleAn iron delivery pathway mediated by a lipocalin Mol Cell 10 1045–1056 Occurrence Handle12453413 Occurrence Handle1:CAS:528:DC%2BD38Xptl2ksLY%3D Occurrence Handle10.1016/S1097-2765(02)00710-4

    Article  PubMed  CAS  Google Scholar 

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  1. The Granulocyte Research Laboratory, Department of Hematology, University of Copenhagen, Rigshospitalet-4042, 9 Blegdamsvej, Copenhagen Ø, DK 2200, Denmark

    Niels Borregaard & Jack B. Cowland

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  1. Niels Borregaard
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  2. Jack B. Cowland
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Correspondence to Niels Borregaard.

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Borregaard, N., Cowland, J.B. Neutrophil Gelatinase-associated Lipocalin, a Siderophore-binding Eukaryotic Protein. Biometals 19, 211–215 (2006). https://doi.org/10.1007/s10534-005-3251-7

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  • DOI: https://doi.org/10.1007/s10534-005-3251-7

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