Fast Multi-blind Modification Search Through Tandem Mass Spectrometry

Overview

Journal Mol Cell Proteomics

Specialties Biochemistry
Cell Biology
Molecular Biology

Date 2011 Dec 22

PMID 22186716

Citations 67

Authors

Seungjin Na

Nuno Bandeira

Eunok Paek

Affiliations

Soon will be listed here.

Abstract

With great biological interest in post-translational modifications (PTMs), various approaches have been introduced to identify PTMs using MS/MS. Recent developments for PTM identification have focused on an unrestrictive approach that searches MS/MS spectra for all known and possibly even unknown types of PTMs at once. However, the resulting expanded search space requires much longer search time and also increases the number of false positives (incorrect identifications) and false negatives (missed true identifications), thus creating a bottleneck in high throughput analysis. Here we introduce MODa, a novel "multi-blind" spectral alignment algorithm that allows for fast unrestrictive PTM searches with no limitation on the number of modifications per peptide while featuring over an order of magnitude speedup in relation to existing approaches. We demonstrate the sensitivity of MODa on human shotgun proteomics data where it reveals multiple mutations, a wide range of modifications (including glycosylation), and evidence for several putative novel modifications. Based on the reported findings, we argue that the efficiency and sensitivity of MODa make it the first unrestrictive search tool with the potential to fully replace conventional restrictive identification of proteomics mass spectrometry data.

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References

Savitski M, Nielsen M, Zubarev R . ModifiComb, a new proteomic tool for mapping substoichiometric post-translational modifications, finding novel types of modifications, and fingerprinting complex protein mixtures. Mol Cell Proteomics. 2006; 5(5):935-48. DOI: 10.1074/mcp.T500034-MCP200. View

Nielsen M, Savitski M, Zubarev R . Extent of modifications in human proteome samples and their effect on dynamic range of analysis in shotgun proteomics. Mol Cell Proteomics. 2006; 5(12):2384-91. DOI: 10.1074/mcp.M600248-MCP200. View

Steen H, Mann M . The ABC's (and XYZ's) of peptide sequencing. Nat Rev Mol Cell Biol. 2004; 5(9):699-711. DOI: 10.1038/nrm1468. View

Tabb D, Saraf A, Yates 3rd J . GutenTag: high-throughput sequence tagging via an empirically derived fragmentation model. Anal Chem. 2003; 75(23):6415-21. PMC: 2915448. DOI: 10.1021/ac0347462. View

Mann M, Jensen O . Proteomic analysis of post-translational modifications. Nat Biotechnol. 2003; 21(3):255-61. DOI: 10.1038/nbt0303-255. View

Wilmarth P, Tanner S, Dasari S, Nagalla S, Riviere M, Bafna V . Age-related changes in human crystallins determined from comparative analysis of post-translational modifications in young and aged lens: does deamidation contribute to crystallin insolubility?. J Proteome Res. 2006; 5(10):2554-66. PMC: 2536618. DOI: 10.1021/pr050473a. View

. A haplotype map of the human genome. Nature. 2005; 437(7063):1299-320. PMC: 1880871. DOI: 10.1038/nature04226. View

Searle B, Dasari S, Wilmarth P, Turner M, Reddy A, David L . Identification of protein modifications using MS/MS de novo sequencing and the OpenSea alignment algorithm. J Proteome Res. 2005; 4(2):546-54. DOI: 10.1021/pr049781j. View

Chalkley R, Baker P, Medzihradszky K, Lynn A, Burlingame A . In-depth analysis of tandem mass spectrometry data from disparate instrument types. Mol Cell Proteomics. 2008; 7(12):2386-98. PMC: 2596346. DOI: 10.1074/mcp.M800021-MCP200. View

10.

Bandeira N, Tsur D, Frank A, Pevzner P . Protein identification by spectral networks analysis. Proc Natl Acad Sci U S A. 2007; 104(15):6140-5. PMC: 1851064. DOI: 10.1073/pnas.0701130104. View

11.

Bern M, Kil Y . Comment on "Unbiased statistical analysis for multi-stage proteomic search strategies". J Proteome Res. 2011; 10(4):2123-7. PMC: 3613568. DOI: 10.1021/pr101143m. View

12.

Geoghegan K, Hoth L, Tan D, Borzilleri K, Withka J, Boyd J . Cyclization of N-terminal S-carbamoylmethylcysteine causing loss of 17 Da from peptides and extra peaks in peptide maps. J Proteome Res. 2003; 1(2):181-7. DOI: 10.1021/pr025503d. View

13.

Tanner S, Shu H, Frank A, Wang L, Zandi E, Mumby M . InsPecT: identification of posttranslationally modified peptides from tandem mass spectra. Anal Chem. 2005; 77(14):4626-39. DOI: 10.1021/ac050102d. View

14.

Plotnikova O, Kondrashov F, Vlasov P, Grigorenko A, Ginter E, Rogaev E . Conversion and compensatory evolution of the gamma-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am J Hum Genet. 2007; 81(1):32-43. PMC: 1950927. DOI: 10.1086/518616. View

15.

Elias J, Gygi S . Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat Methods. 2007; 4(3):207-14. DOI: 10.1038/nmeth1019. View

16.

Ong S, Mittler G, Mann M . Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat Methods. 2005; 1(2):119-26. DOI: 10.1038/nmeth715. View

17.

Paizs B, Suhai S . Fragmentation pathways of protonated peptides. Mass Spectrom Rev. 2004; 24(4):508-48. DOI: 10.1002/mas.20024. View

18.

Dasari S, Chambers M, Slebos R, Zimmerman L, Ham A, Tabb D . TagRecon: high-throughput mutation identification through sequence tagging. J Proteome Res. 2010; 9(4):1716-26. PMC: 2859315. DOI: 10.1021/pr900850m. View

19.

Na S, Paek E, Lee C . CIFTER: automated charge-state determination for peptide tandem mass spectra. Anal Chem. 2008; 80(5):1520-8. DOI: 10.1021/ac702038q. View

20.

Perkins D, Pappin D, Creasy D, Cottrell J . Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis. 1999; 20(18):3551-67. DOI: 10.1002/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2. View