{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:39:49Z","timestamp":1790789989773,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2014,6,26]],"date-time":"2014-06-26T00:00:00Z","timestamp":1403740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Helicobacter pylori causes severe diseases, such as chronic gastritis, peptic ulcers, and stomach cancers. H. pylori neutrophil-activating protein (HP-NAP) is an iron storage protein that forms a dodecameric shell, promotes the adhesion of neutrophils to endothelial cells, and induces the production of reactive oxygen radicals. HP-NAP belongs to the DNA-protecting proteins under starved conditions (Dps) family, which has significant structural similarities to the dodecameric ferritin family. The crystal structures of the  apo form and metal-ion bound forms, such as iron, zinc, and cadmium, of HP-NAP have been determined. This review focused on the structures and metal-binding properties of HP-NAP. These metal ions bind at the di-nuclear ferroxidase center (FOC) by different coordinating patterns. In comparison with the apo structure, metal loading causes a series of conformational changes in conserved residues among HP-NAP and Dps proteins (Trp26, Asp52, and Glu56) at the FOC. HP-NAP forms a spherical dodecamer with  23 symmetry including two kinds of pores. Metal ions have been identified around one of the pores; therefore, the negatively-charged pore is suitable for the passage of metal ions.<\/jats:p>","DOI":"10.3390\/biom4030600","type":"journal-article","created":{"date-parts":[[2014,6,26]],"date-time":"2014-06-26T11:03:52Z","timestamp":1403780632000},"page":"600-615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structures and Metal-Binding Properties of Helicobacter pylori Neutrophil-Activating Protein with a Di-Nuclear Ferroxidase Center"],"prefix":"10.3390","volume":"4","author":[{"given":"Hideshi","family":"Yokoyama","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Fujii","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/S0140-6736(84)91816-6","article-title":"Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration","volume":"1","author":"Marshall","year":"1984","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1128\/CMR.10.4.720","article-title":"Helicobacter pylori","volume":"10","author":"Dunn","year":"1997","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/oxfordjournals.epirev.a018040","article-title":"Helicobacter pylori: Epidemiology and routes of transmission","volume":"22","author":"Brown","year":"2000","journal-title":"Epidemiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1086\/516077","article-title":"Helicobacter pylori gastritis, peptic ulcer, and gastric cancer: Clinical and molecular aspects","volume":"25","author":"Goodwin","year":"1997","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1126\/science.284.5418.1328","article-title":"Helicobacter pylori virulence and genetic geography","volume":"284","author":"Covacci","year":"1999","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/35073084","article-title":"Living dangerously: How Helicobacter pylori survives in the human stomach","volume":"2","author":"Montecucco","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S1286-4579(03)00124-2","article-title":"Molecular and cellular mechanisms of action of the vacuolating cytotoxin (VacA) and neutrophil-activating protein (HP-NAP) virulence factors of Helicobacter pylori","volume":"5","author":"Montecucco","year":"2003","journal-title":"Microbes Infect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1084\/jem.191.9.1467","article-title":"The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor","volume":"191","author":"Satin","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1128\/iai.63.6.2213-2220.1995","article-title":"Characterization of a Helicobacter pylori neutrophil-activating protein","volume":"63","author":"Evans","year":"1995","journal-title":"Infect. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1078\/1438-4221-00165","article-title":"The neutrophil-activating protein of Helicobacter pylori","volume":"291","author":"Dundon","year":"2002","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19067","DOI":"10.1074\/jbc.272.30.19067","article-title":"Carbohydrate binding specificity of the neutrophil-activating protein of Helicobacter pylori","volume":"272","author":"Teneberg","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1128\/IAI.66.2.444-447.1998","article-title":"Neutrophil-activating protein mediates adhesion of Helicobacter pylori to sulfated carbohydrates on high-molecular-weight salivary mucin","volume":"66","author":"Namavar","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1086\/319280","article-title":"Helicobacter pylori neutrophil-activating protein stimulates tissue factor and plasminogen activator inhibitor-2 production by human blood mononuclear cells","volume":"183","author":"Montemurro","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.4049\/jimmunol.178.3.1312","article-title":"The neutrophil-activating protein of Helicobacter pylori crosses endothelia to promote neutrophil adhesion in vivo","volume":"178","author":"Polenghi","year":"2007","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/1521-4141(200203)32:3<671::AID-IMMU671>3.0.CO;2-5","article-title":"The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a potent stimulant of mast cells","volume":"32","author":"Montemurro","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1172\/JCI27177","article-title":"The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses","volume":"116","author":"Amedei","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.1574-695X.2007.00258.x","article-title":"The neutrophil-activating protein of Helicobacter pylori (HP-NAP) as an immune modulating agent","volume":"50","author":"Amedei","year":"2007","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.toxicon.2009.09.020","article-title":"The immune modulating activity of the Helicobacter pylori HP-NAP: Friend or foe?","volume":"56","year":"2010","journal-title":"Toxicon"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1146\/annurev.immunol.19.1.523","article-title":"The design of vaccines against Helicobacter pylori and their development","volume":"19","author":"Covacci","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1523-5378.2007.00478.x","article-title":"The current status of Helicobacter pylori vaccines: A review","volume":"12","author":"Kabir","year":"2007","journal-title":"Helicobacter"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1053\/j.gastro.2008.05.054","article-title":"Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: A phase I study","volume":"135","author":"Malfertheiner","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1046\/j.1365-2958.1999.01584.x","article-title":"The Helicobacter pylori neutrophil-activating protein is an iron-binding protein with dodecameric structure","volume":"34","author":"Tonello","year":"1999","journal-title":"Mol. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/nsb0498-294","article-title":"The crystal structure of Dps, a ferritin homolog that binds and protects DNA","volume":"5","author":"Grant","year":"1998","journal-title":"Nat. Struct. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/71236","article-title":"The dodecameric ferritin from Listeria innocua contains a novel intersubunit iron-binding site","volume":"7","author":"Ilari","year":"2000","journal-title":"Nat. Struct. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6839","DOI":"10.1128\/IAI.00991-06","article-title":"Dual roles of Helicobacter pylori NapA in inducing and combating oxidative stress","volume":"74","author":"Wang","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1099\/jmm.0.05070-0","article-title":"NapA protects Helicobacter pylori from oxidative stress damage, and its production is influenced by the ferric uptake regulator","volume":"52","author":"Cooksley","year":"2003","journal-title":"J. Med. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/21918","article-title":"DNA protection by stress-induced biocrystallization","volume":"400","author":"Wolf","year":"1999","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00018-009-0168-2","article-title":"Dps-like proteins: Structural and functional insights into a versatile protein family","volume":"67","author":"Haikarainen","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0005-2728(96)00022-9","article-title":"The ferritins: Molecular properties, iron storage function and cellular regulation","volume":"1275","author":"Harrison","year":"1996","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0022-2836(02)00879-3","article-title":"Structure of the neutrophil-activating protein from Helicobacter pylori","volume":"323","author":"Zanotti","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.bbagen.2010.03.019","article-title":"X-ray structures of ferritins and related proteins","volume":"1800","author":"Crichton","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1107\/S1744309110043113","article-title":"Structures of the SEp22 dodecamer, a Dps-like protein from Salmonella enterica subsp. enterica serovar Enteritidis","volume":"67","author":"Miyamoto","year":"2011","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1107\/S1744309111052675","article-title":"A new crystal lattice structure of Helicobacter pylori neutrophil-activating protein (HP-NAP)","volume":"68","author":"Tsuruta","year":"2012","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.bbrc.2012.05.073","article-title":"Crystal structure of Helicobacter pylori neutrophil-activating protein with a di-nuclear ferroxidase center in a zinc or cadmium-bound form","volume":"422","author":"Yokoyama","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"W116","DOI":"10.1093\/nar\/gkl282","article-title":"CASTp: Computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues","volume":"34","author":"Dundas","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0022-2836(03)00466-2","article-title":"The multi-layered structure of Dps with a novel di-nuclear ferroxidase center","volume":"329","author":"Ren","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0162-0134(98)10042-9","article-title":"Coordination geometries of selected transition metal ions (Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Hg2+) in metalloproteins","volume":"71","year":"1998","journal-title":"J. Inorg. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1021\/bi002661e","article-title":"High resolution X-ray structures of different metal-substituted forms of phosphotriesterase from Pseudomonas diminuta","volume":"40","author":"Benning","year":"2001","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1107\/S0907444997000875","article-title":"Structure of rabbit muscle phosphoglucomutase refined at 2.4 \u00c5 resolution","volume":"53","author":"Liu","year":"1997","journal-title":"Acta Crystallogr. Sect. D Biol.Crystallogr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1002\/pro.5560041001","article-title":"Structural analysis of zinc substitutions in the active site of thermolysin","volume":"4","author":"Holland","year":"1995","journal-title":"ProteinSci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.bbrc.2010.06.071","article-title":"Structural characterization and biological implications of di-zinc binding in the ferroxidase center of Streptococcus pyogenes Dpr","volume":"398","author":"Haikarainen","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1110\/ps.036236.108","article-title":"Structural basis of the zinc- and terbium-mediated inhibition of ferroxidase activity in Dps ferritin-like proteins","volume":"17","author":"Havukainen","year":"2008","journal-title":"ProteinSci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15093","DOI":"10.1074\/jbc.M112378200","article-title":"Structure of two iron-binding proteins from Bacillus anthracis","volume":"277","author":"Papinutto","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/s00775-006-0142-5","article-title":"The crystal structure of Deinococcus radiodurans Dps protein (DR2263) reveals the presence of a novel metal centre in the N terminus","volume":"11","author":"Mitchell","year":"2006","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10815","DOI":"10.1021\/bi060782u","article-title":"Structure of the DPS-like protein from Sulfolobus solfataricus reveals a bacterioferritin-like dimetal binding site within a DPS-like dodecameric assembly","volume":"45","author":"Gauss","year":"2006","journal-title":"Biochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.jmb.2006.11.032","article-title":"The crystal structure of the Dps2 from Deinococcus radiodurans reveals an unusual pore profile with a non-specific metal binding site","volume":"371","author":"Cuypers","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4990","DOI":"10.1021\/bi002593w","article-title":"Importance of basic residues and quaternary structure in the function of MIP-1\u03b2: CCR5 binding and cell surface sugar interactions","volume":"40","author":"Laurence","year":"2001","journal-title":"Biochemistry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20110","DOI":"10.1016\/S0021-9258(17)32134-8","article-title":"Subunit association and structural analysis of platelet basic protein and related proteins investigated by 1H-NMR spectroscopy and circular dichroism","volume":"269","author":"Yang","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1111\/j.1742-4658.2007.06201.x","article-title":"Helicobacter pylori neutrophil-activating protein activates neutrophils by its C-terminal region even without dodecamer formation, which is a prerequisite for DNA protection\u2014Novel approaches against Helicobacter pylori inflammation","volume":"275","author":"Kottakis","year":"2008","journal-title":"FEBS J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1016\/j.bbapap.2010.09.004","article-title":"Structure and immunomodulatory property relationship in NapA of Borrelia burgdorferi","volume":"1804","author":"Codolo","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1002\/art.23972","article-title":"Borrelia burgdorferi NapA-driven Th17 cell inflammation in lyme arthritis","volume":"58","author":"Codolo","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nri1391","article-title":"Toll-like receptor signalling","volume":"4","author":"Akira","year":"2004","journal-title":"Nat. Rev. Immunol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/4\/3\/600\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:12:59Z","timestamp":1760217179000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/4\/3\/600"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,26]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,9]]}},"alternative-id":["biom4030600"],"URL":"https:\/\/doi.org\/10.3390\/biom4030600","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,26]]}}}