{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T13:37:57Z","timestamp":1760708277939},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2011,2,28]],"date-time":"2011-02-28T00:00:00Z","timestamp":1298851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Metal-containing proteins comprise a diverse and sizable category within the proteomes of organisms, ranging from proteins that use metals to catalyze reactions to proteins in which metals play key structural roles. Unfortunately, reliably predicting that a protein will contain a specific metal from its amino acid sequence is not currently possible. We recently developed a generally-applicable experimental technique for finding metalloproteins on a genome-wide scale. Applying this metal-directed protein purification approach (ICP-MS and MS\/MS based) to the prototypical microbe <jats:italic>Pyrococcus furiosus<\/jats:italic> conclusively demonstrated the extent and diversity of the uncharacterized portion of microbial metalloproteomes since a majority of the observed metal peaks could not be assigned to known or predicted metalloproteins. However, even using this technique, it is not technically feasible to purify to homogeneity all metalloproteins in an organism. In order to address these limitations and complement the metal-directed protein purification, we developed a computational infrastructure and statistical methodology to aid in the pursuit and identification of novel metalloproteins.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We demonstrate that our methodology enables predictions of metal-protein interactions using an experimental data set derived from a chromatography fractionation experiment in which 870 proteins and 10 metals were measured over 2,589 fractions. For each of the 10 metals, cobalt, iron, manganese, molybdenum, nickel, lead, tungsten, uranium, vanadium, and zinc, clusters of proteins frequently occurring in metal peaks (of a specific metal) within the fractionation space were defined. This resulted in predictions that there are from 5 undiscovered vanadium- to 13 undiscovered cobalt-containing proteins in <jats:italic>Pyrococcus furiosus<\/jats:italic>. Molybdenum and nickel were chosen for additional assessment producing lists of genes predicted to encode metalloproteins or metalloprotein subunits, 22 for nickel including seven from known nickel-proteins, and 20 for molybdenum including two from known molybdo-proteins. The uncharacterized proteins are prime candidates for metal-based purification or recombinant approaches to validate these predictions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We conclude that the largely uncharacterized extent of native metalloproteomes can be revealed through analysis of the co-occurrence of metals and proteins across a fractionation space. This can significantly impact our understanding of metallobiochemistry, disease mechanisms, and metal toxicity, with implications for bioremediation, medicine and other fields.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-12-64","type":"journal-article","created":{"date-parts":[[2011,3,2]],"date-time":"2011-03-02T00:08:07Z","timestamp":1299024487000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A Computational Framework for Proteome-Wide Pursuit and Prediction of Metalloproteins using ICP-MS and MS\/MS Data"],"prefix":"10.1186","volume":"12","author":[{"given":"W Andrew","family":"Lancaster","sequence":"first","affiliation":[]},{"given":"Jeremy L","family":"Praissman","sequence":"additional","affiliation":[]},{"suffix":"II","given":"Farris L","family":"Poole","sequence":"additional","affiliation":[]},{"given":"Aleksandar","family":"Cvetkovic","sequence":"additional","affiliation":[]},{"given":"Angeli Lal","family":"Menon","sequence":"additional","affiliation":[]},{"given":"Joseph W","family":"Scott","sequence":"additional","affiliation":[]},{"suffix":"Jr","given":"Francis E","family":"Jenney","sequence":"additional","affiliation":[]},{"given":"Michael P","family":"Thorgersen","sequence":"additional","affiliation":[]},{"given":"Ewa","family":"Kalisiak","sequence":"additional","affiliation":[]},{"given":"Junefredo V","family":"Apon","sequence":"additional","affiliation":[]},{"given":"Sunia A","family":"Trauger","sequence":"additional","affiliation":[]},{"given":"Gary","family":"Siuzdak","sequence":"additional","affiliation":[]},{"given":"John A","family":"Tainer","sequence":"additional","affiliation":[]},{"given":"Michael W","family":"W Adams","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2011,2,28]]},"reference":[{"key":"4439_CR1","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1039\/b713633c","volume":"38","author":"S Mounicou","year":"2009","unstructured":"Mounicou S, Szpunar J, Lobinski R: Metallomics: the concept and methodology. Chemical Society Reviews 2009, 38: 1119\u20131138. 10.1039\/b713633c","journal-title":"Chemical Society Reviews"},{"key":"4439_CR2","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/nature08300","volume":"460","author":"KJ Waldron","year":"2009","unstructured":"Waldron KJ, Rutherford JC, Ford D, Robinson NJ: Metalloproteins and metal sensing. Nature 2009, 460: 823\u2013830. 10.1038\/nature08300","journal-title":"Nature"},{"key":"4439_CR3","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1021\/ar900015x","volume":"42","author":"C Andreini","year":"2009","unstructured":"Andreini C, Bertini I, Rosato A: Metalloproteomes: A Bioinformatic Approach. Acc Chem Res 2009, 42: 1471\u20131479. 10.1021\/ar900015x","journal-title":"Acc Chem Res"},{"key":"4439_CR4","doi-asserted-by":"publisher","first-page":"10567","DOI":"10.1073\/pnas.0912491107","volume":"107","author":"CL Dupont","year":"2010","unstructured":"Dupont CL, Butcher A, Valas RE, Bourne PE, Caetano-Anolles G: History of biological metal utilization inferred through phylogenomic analysis of protein structures. Proc Natl Acad Sci USA 2010, 107: 10567\u201310572. 10.1073\/pnas.0912491107","journal-title":"Proc Natl Acad Sci USA"},{"key":"4439_CR5","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/nrmicro2057","volume":"7","author":"KJ Waldron","year":"2009","unstructured":"Waldron KJ, Robinson NJ: How do bacterial cells ensure that metalloproteins get the correct metal? Nat Rev Microbiol 2009, 7: 25\u201335. 10.1038\/nrmicro2057","journal-title":"Nat Rev Microbiol"},{"key":"4439_CR6","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1038\/nature09265","volume":"466","author":"A Cvetkovic","year":"2010","unstructured":"Cvetkovic A, Menon AL, Thorgersen MP, Scott JW, Poole FL, Jenney FE Jr, Lancaster WA, Praissman JL, Shanmukh S, Vaccaro BJ, et al.: Microbial metalloproteomes are largely uncharacterized. Nature 2010, 466: 779\u2013782. 10.1038\/nature09265","journal-title":"Nature"},{"key":"4439_CR7","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1074\/mcp.M800246-MCP200","volume":"8","author":"AL Menon","year":"2009","unstructured":"Menon AL, Poole FL, Cvetkovic A, Trauger SA, Kalisiak E, Scott JW, Shanmukh S, Praissman J, Jenney FE Jr, Wikoff WR, et al.: Novel multiprotein complexes identified in the hyperthermophilic archaeon Pyrococcus furiosus by non-denaturing fractionation of the native proteome. Mol Cell Proteomics 2009, 8: 735\u2013751. 10.1074\/mcp.M800246-MCP200","journal-title":"Mol Cell Proteomics"},{"key":"4439_CR8","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1007\/s00253-010-2695-z","volume":"87","author":"G Haferburg","year":"2010","unstructured":"Haferburg G, Kothe E: Metallomics: lessons for metalliferous soil remediation. Appl Microbiol Biotechnol 2010, 87: 1271\u20131280. 10.1007\/s00253-010-2695-z","journal-title":"Appl Microbiol Biotechnol"},{"key":"4439_CR9","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1038\/nature07340","volume":"455","author":"S Tottey","year":"2008","unstructured":"Tottey S, Waldron KJ, Firbank SJ, Reale B, Bessant C, Sato K, Cheek TR, Gray J, Banfield MJ, Dennison C, Robinson NJ: Protein-folding location can regulate manganese-binding versus copper- or zinc-binding. Nature 2008, 455: 1138\u20131142. 10.1038\/nature07340","journal-title":"Nature"},{"key":"4439_CR10","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1007\/s00775-009-0477-9","volume":"14","author":"AM Sevcenco","year":"2009","unstructured":"Sevcenco AM, Krijger GC, Pinkse MW, Verhaert PD, Hagen WR, Hagedoorn PL: Development of a generic approach to native metalloproteomics: application to the quantitative identification of soluble copper proteins in Escherichia coli . J Biol Inorg Chem 2009, 14: 631\u2013640. 10.1007\/s00775-009-0477-9","journal-title":"J Biol Inorg Chem"},{"key":"4439_CR11","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1093\/protein\/gzn015","volume":"21","author":"C Kehl","year":"2008","unstructured":"Kehl C, Simms AM, Toofanny RD, Daggett V: Dynameomics: a multi-dimensional analysis-optimized database for dynamic protein data. Protein Eng Des Sel 2008, 21: 379\u2013386. 10.1093\/protein\/gzn015","journal-title":"Protein Eng Des Sel"},{"key":"4439_CR12","doi-asserted-by":"publisher","first-page":"D211","DOI":"10.1093\/nar\/gkn785","volume":"37","author":"S Hunter","year":"2009","unstructured":"Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, Bork P, Das U, Daugherty L, Duquenne L, et al.: InterPro: the integrative protein signature database. Nucleic Acids Res 2009, 37: D211\u2013215. 10.1093\/nar\/gkn785","journal-title":"Nucleic Acids Res"},{"key":"4439_CR13","unstructured":"R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3\u2013900051\u201307\u20130[http:\/\/www.R-project.org]"},{"key":"4439_CR14","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1093\/bioinformatics\/btm563","volume":"24","author":"P Langfelder","year":"2008","unstructured":"Langfelder P, Zhang B, Horvath S: Defining clusters from a hierarchical cluster tree: the Dynamic Tree Cut package for R. Bioinformatics 2008, 24: 719\u2013720. 10.1093\/bioinformatics\/btm563","journal-title":"Bioinformatics"},{"key":"4439_CR15","doi-asserted-by":"crossref","first-page":"Article17","DOI":"10.2202\/1544-6115.1128","volume":"4","author":"B Zhang","year":"2005","unstructured":"Zhang B, Horvath S: A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 2005, 4: Article17.","journal-title":"Stat Appl Genet Mol Biol"},{"key":"4439_CR16","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1287\/moor.4.3.233","volume":"4","author":"V Chvatal","year":"1979","unstructured":"Chvatal V: A Greedy Heuristic for the Set-Covering Problem. Mathematics of operations research 1979, 4: 233\u2013235. 10.1287\/moor.4.3.233","journal-title":"Mathematics of operations research"},{"key":"4439_CR17","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1007\/s00775-008-0404-5","volume":"13","author":"C Andreini","year":"2008","unstructured":"Andreini C, Bertini I, Cavallaro G, Holliday GL, Thornton JM: Metal ions in biological catalysis: from enzyme databases to general principles. Journal Of Biological Inorganic Chemistry 2008, 13: 1205\u20131218. 10.1007\/s00775-008-0404-5","journal-title":"Journal Of Biological Inorganic Chemistry"},{"key":"4439_CR18","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1093\/jb\/mvh009","volume":"135","author":"A Yamaguchi","year":"2004","unstructured":"Yamaguchi A, Iida K, Matsui N, Tomoda S, Yura K, Go M: Het-PDB Navi.: a database for protein-small molecule interactions. J Biochem 2004, 135: 79\u201384. 10.1093\/jb\/mvh009","journal-title":"J Biochem"},{"key":"4439_CR19","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1039\/b906690j","volume":"27","author":"Z Xiao","year":"2010","unstructured":"Xiao Z, Wedd AG: The challenges of determining metal-protein affinities. Nat Prod Rep 2010, 27: 768\u2013789. 10.1039\/b906690j","journal-title":"Nat Prod Rep"},{"key":"4439_CR20","doi-asserted-by":"publisher","first-page":"D61","DOI":"10.1093\/nar\/gkl842","volume":"35","author":"KD Pruitt","year":"2007","unstructured":"Pruitt KD, Tatusova T, Maglott DR: NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 2007, 35: D61\u201365. 10.1093\/nar\/gkl842","journal-title":"Nucleic Acids Res"},{"key":"4439_CR21","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.jmb.2009.09.030","volume":"394","author":"S Watanabe","year":"2009","unstructured":"Watanabe S, Arai T, Matsumi R, Atomi H, Imanaka T, Miki K: Crystal structure of HypA, a nickel-binding metallochaperone for [NiFe] hydrogenase maturation. J Mol Biol 2009, 394: 448\u2013459. 10.1016\/j.jmb.2009.09.030","journal-title":"J Mol Biol"},{"key":"4439_CR22","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1146\/annurev.biophys.37.032807.125811","volume":"37","author":"T Dudev","year":"2008","unstructured":"Dudev T, Lim C: Metal Binding Affinity and Selectivity in Metalloproteins: Insights from Computational Studies. Annual Review of Biophysics 2008, 37: 97\u2013116. 10.1146\/annurev.biophys.37.032807.125811","journal-title":"Annual Review of Biophysics"},{"key":"4439_CR23","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/S0076-6879(01)34457-9","volume":"334","author":"FE Jenney Jr","year":"2001","unstructured":"Jenney FE Jr, Adams MW: Rubredoxin from Pyrococcus furiosus . Methods Enzymol 2001, 334: 45\u201355. full_text","journal-title":"Methods Enzymol"},{"key":"4439_CR24","doi-asserted-by":"publisher","first-page":"10071","DOI":"10.1021\/bi050472w","volume":"44","author":"J Sivaraman","year":"2005","unstructured":"Sivaraman J, Myers RS, Boju L, Sulea T, Cygler M, Jo Davisson V, Schrag JD: Crystal structure of Methanobacterium thermoautotrophicum phosphoribosyl-AMP cyclohydrolase HisI. Biochemistry 2005, 44: 10071\u201310080. 10.1021\/bi050472w","journal-title":"Biochemistry"},{"key":"4439_CR25","doi-asserted-by":"publisher","first-page":"2077","DOI":"10.1128\/JB.187.6.2077-2083.2005","volume":"187","author":"SV Story","year":"2005","unstructured":"Story SV, Shah C, Jenney FE Jr, Adams MW: Characterization of a novel zinc-containing, lysine-specific aminopeptidase from the hyperthermophilic archaeon Pyrococcus furiosus . J Bacteriol 2005, 187: 2077\u20132083. 10.1128\/JB.187.6.2077-2083.2005","journal-title":"J Bacteriol"},{"key":"4439_CR26","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.cbpa.2006.01.034","volume":"10","author":"CD Brondino","year":"2006","unstructured":"Brondino CD, Romao MJ, Moura I, Moura JJ: Molybdenum and tungsten enzymes: the xanthine oxidase family. Curr Opin Chem Biol 2006, 10: 109\u2013114. 10.1016\/j.cbpa.2006.01.034","journal-title":"Curr Opin Chem Biol"},{"key":"4439_CR27","doi-asserted-by":"publisher","first-page":"7708","DOI":"10.1073\/pnas.91.16.7708","volume":"91","author":"VN Gladyshev","year":"1994","unstructured":"Gladyshev VN, Khangulov SV, Axley MJ, Stadtman TC: Coordination of selenium to molybdenum in formate dehydrogenase H from Escherichia coli . Proc Natl Acad Sci USA 1994, 91: 7708\u20137711. 10.1073\/pnas.91.16.7708","journal-title":"Proc Natl Acad Sci USA"},{"key":"4439_CR28","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0079-6107(97)00022-9","volume":"68","author":"MJ Romao","year":"1997","unstructured":"Romao MJ, Knablein J, Huber R, Moura JJ: Structure and function of molybdopterin containing enzymes. Prog Biophys Mol Biol 1997, 68: 121\u2013144. 10.1016\/S0079-6107(97)00022-9","journal-title":"Prog Biophys Mol Biol"},{"key":"4439_CR29","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/nature08302","volume":"460","author":"G Schwarz","year":"2009","unstructured":"Schwarz G, Mendel RR, Ribbe MW: Molybdenum cofactors, enzymes and pathways. Nature 2009, 460: 839\u2013847. 10.1038\/nature08302","journal-title":"Nature"},{"key":"4439_CR30","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nbt1270","volume":"25","author":"P Lu","year":"2007","unstructured":"Lu P, Vogel C, Wang R, Yao X, Marcotte EM: Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol 2007, 25: 117\u2013124. 10.1038\/nbt1270","journal-title":"Nat Biotechnol"},{"key":"4439_CR31","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1074\/mcp.M500230-MCP200","volume":"5","author":"JC Silva","year":"2006","unstructured":"Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ: Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol Cell Proteomics 2006, 5: 144\u2013156.","journal-title":"Mol Cell Proteomics"},{"key":"4439_CR32","first-page":"840518","volume":"2010","author":"W Zhu","year":"2010","unstructured":"Zhu W, Smith JW, Huang CM: Mass spectrometry-based label-free quantitative proteomics. J Biomed Biotechnol 2010, 2010: 840518.","journal-title":"J Biomed Biotechnol"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-12-64.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/1471-2105-12-64\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-12-64.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T13:19:06Z","timestamp":1630502346000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-12-64"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,2,28]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["4439"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-12-64","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,2,28]]},"assertion":[{"value":"10 October 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"64"}}