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Protein Engineering, Vol. 12, No. 1, 3-9, January 1999
© 1999 Oxford University Press


REVIEW

Machine learning approaches for the prediction of signal peptides and other protein sorting signals

Henrik Nielsen1, Søren Brunak and Gunnar von Heijne2

Center for Biological Sequence Analysis Department of Biotechnology, The Technical University of Denmark, DK-2800 Lyngby, Denmark and 2 Department of Biochemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden

Prediction of protein sorting signals from the sequence of amino acids has great importance in the field of proteomics today. Recently, the growth of protein databases, combined with machine learning approaches, such as neural networks and hidden Markov models, have made it possible to achieve a level of reliability where practical use in, for example automatic database annotation is feasible. In this review, we concentrate on the present status and future perspectives of SignalP, our neural network-based method for prediction of the most well-known sorting signal: the secretory signal peptide. We discuss the problems associated with the use of SignalP on genomic sequences, showing that signal peptide prediction will improve further if integrated with predictions of start codons and transmembrane helices. As a step towards this goal, a hidden Markov model version of SignalP has been developed, making it possible to discriminate between cleaved signal peptides and uncleaved signal anchors. Furthermore, we show how SignalP can be used to characterize putative signal peptides from an archaeon, Methanococcus jannaschii. Finally, we briefly review a few methods for predicting other protein sorting signals and discuss the future of protein sorting prediction in general.

1 To whom correspondence should be addressed


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J. Clin. Microbiol., February 1, 2003; 41(2): 723 - 729.
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D. Muller, D. Lievremont, D. D. Simeonova, J.-C. Hubert, and M.-C. Lett
Arsenite Oxidase aox Genes from a Metal-Resistant {beta}-Proteobacterium
J. Bacteriol., January 1, 2003; 185(1): 135 - 141.
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J. D. H. Jongbloed, H. Antelmann, M. Hecker, R. Nijland, S. Bron, U. Airaksinen, F. Pries, W. J. Quax, J. M. van Dijl, and P. G. Braun
Selective Contribution of the Twin-Arginine Translocation Pathway to Protein Secretion in Bacillus subtilis
J. Biol. Chem., November 8, 2002; 277(46): 44068 - 44078.
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MicrobiologyHome page
A. Bolhuis
Protein transport in the halophilic archaeon Halobacterium sp. NRC-1: a major role for the twin-arginine translocation pathway?
Microbiology, November 1, 2002; 148(11): 3335 - 3346.
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MicrobiologyHome page
J. Tolle, K.-P. Michel, J. Kruip, U. Kahmann, A. Preisfeld, and E. K. Pistorius
Localization and function of the IdiA homologue Slr1295 in the cyanobacterium Synechocystis sp. strain PCC 6803
Microbiology, October 1, 2002; 148(10): 3293 - 3305.
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T. Collins, M.-A. Meuwis, I. Stals, M. Claeyssens, G. Feller, and C. Gerday
A Novel Family 8 Xylanase, Functional and Physicochemical Characterization
J. Biol. Chem., September 13, 2002; 277(38): 35133 - 35139.
[Abstract] [Full Text] [PDF]


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GlycobiologyHome page
D. A. Shagin, E. V. Barsova, E. A. Bogdanova, O. V. Britanova, N. G. Gurskaya, K. A. Lukyanov, M. V. Matz, N. I. Punkova, N. Y. Usman, E. P. Kopantzev, et al.
Identification and characterization of a new family of C-type lectin-like genes from planaria Girardia tigrina
Glycobiology, August 1, 2002; 12(8): 463 - 472.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
P. Mallick, D. R. Boutz, D. Eisenberg, and T. O. Yeates
Genomic evidence that the intracellular proteins of archaeal microbes contain disulfide bonds
PNAS, July 23, 2002; 99(15): 9679 - 9684.
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J. Biol. Chem.Home page
Y.-Y. Chen, K. J. Cross, R. A. Paolini, J. E. Fielding, N. Slakeski, and E. C. Reynolds
CPG70 Is a Novel Basic Metallocarboxypeptidase with C-terminal Polycystic Kidney Disease Domains from Porphyromonas gingivalis
J. Biol. Chem., June 21, 2002; 277(26): 23433 - 23440.
[Abstract] [Full Text] [PDF]


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J. Virol.Home page
A. J. Sanchez, M. J. Vincent, and S. T. Nichol
Characterization of the Glycoproteins of Crimean-Congo Hemorrhagic Fever Virus
J. Virol., June 14, 2002; 76(14): 7263 - 7275.
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Infect. Immun.Home page
K. Van Dellen, S. K. Ghosh, P. W. Robbins, B. Loftus, and J. Samuelson
Entamoeba histolytica Lectins Contain Unique 6-Cys or 8-Cys Chitin-Binding Domains
Infect. Immun., June 1, 2002; 70(6): 3259 - 3263.
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Infect. Immun.Home page
C. Biondo, C. Beninati, D. Delfino, M. Oggioni, G. Mancuso, A. Midiri, M. Bombaci, G. Tomaselli, and G. Teti
Identification and Cloning of a Cryptococcal Deacetylase That Produces Protective Immune Responses
Infect. Immun., May 1, 2002; 70(5): 2383 - 2391.
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Genome ResHome page
Q. Bao, Y. Tian, W. Li, Z. Xu, Z. Xuan, S. Hu, W. Dong, J. Yang, Y. Chen, Y. Xue, et al.
A Complete Sequence of the T. tengcongensis Genome
Genome Res., May 1, 2002; 12(5): 689 - 700.
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EndocrinologyHome page
M. R. John, M. Arai, D. A. Rubin, K. B. Jonsson, and H. Juppner
Identification and Characterization of the Murine and Human Gene Encoding the Tuberoinfundibular Peptide of 39 Residues
Endocrinology, March 1, 2002; 143(3): 1047 - 1057.
[Abstract] [Full Text] [PDF]


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M. Schubert, U. A. Petersson, B. J. Haas, C. Funk, W. P. Schroder, and T. Kieselbach
Proteome Map of the Chloroplast Lumen of Arabidopsis thaliana
J. Biol. Chem., March 1, 2002; 277(10): 8354 - 8365.
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J. Cell Sci.Home page
U. Bohme and G. A. M. Cross
Mutational analysis of the variant surface glycoprotein GPI-anchor signal sequence in Trypanosoma brucei
J. Cell Sci., February 15, 2002; 115(4): 805 - 816.
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Nucleic Acids ResHome page
A. Bateman, E. Birney, L. Cerruti, R. Durbin, L. Etwiller, S. R. Eddy, S. Griffiths-Jones, K. L. Howe, M. Marshall, and E. L. L. Sonnhammer
The Pfam Protein Families Database
Nucleic Acids Res., January 1, 2002; 30(1): 276 - 280.
[Abstract] [Full Text] [PDF]


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Plant CellHome page
J.-B. Peltier, O. Emanuelsson, D. E. Kalume, J. Ytterberg, G. Friso, A. Rudella, D. A. Liberles, L. Soderberg, P. Roepstorff, G. von Heijne, et al.
Central Functions of the Lumenal and Peripheral Thylakoid Proteome of Arabidopsis Determined by Experimentation and Genome-Wide Prediction
PLANT CELL, January 1, 2002; 14(1): 211 - 236.
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Nucleic Acids ResHome page
Y. Fan, C. Y. Wu, C. W. Chen, T. W. Chang, and C. Lim
Preparing a human membrane and secreted protein-enriched cDNA library using PCR primers derived from a genomic database
Nucleic Acids Res., November 15, 2001; 29(22): e114 - e114.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
Y. Hashimoto, T. Niikura, H. Tajima, T. Yasukawa, H. Sudo, Y. Ito, Y. Kita, M. Kawasumi, K. Kouyama, M. Doyu, et al.
A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta
PNAS, May 22, 2001; 98(11): 6336 - 6341.
[Abstract] [Full Text] [PDF]


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B. S. Davis, G.-J. J. Chang, B. Cropp, J. T. Roehrig, D. A. Martin, C. J. Mitchell, R. Bowen, and M. L. Bunning
West Nile Virus Recombinant DNA Vaccine Protects Mouse and Horse from Virus Challenge and Expresses In Vitro a Noninfectious Recombinant Antigen That Can Be Used in Enzyme-Linked Immunosorbent Assays
J. Virol., May 1, 2001; 75(9): 4040 - 4047.
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Antimicrob. Agents Chemother.Home page
P. S. Mercuri, F. Bouillenne, L. Boschi, J. Lamotte-Brasseur, G. Amicosante, B. Devreese, J. van Beeumen, J.-M. Frère, G. M. Rossolini, and M. Galleni
Biochemical Characterization of the FEZ-1 Metallo-{beta}-Lactamase of Legionella gormanii ATCC 33297T Produced in Escherichia coli
Antimicrob. Agents Chemother., April 1, 2001; 45(4): 1254 - 1262.
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M. Göttfert, S. Röthlisberger, C. Kündig, C. Beck, R. Marty, and H. Hennecke
Potential Symbiosis-Specific Genes Uncovered by Sequencing a 410-Kilobase DNA Region of the Bradyrhizobium japonicum Chromosome
J. Bacteriol., February 15, 2001; 183(4): 1405 - 1412.
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Protein Eng Des SelHome page
K.-C. Chou
Using subsite coupling to predict signal peptides
Protein Eng. Des. Sel., February 1, 2001; 14(2): 75 - 79.
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Protein Eng Des SelHome page
B. Eisenhaber, P. Bork, and F. Eisenhaber
Post-translational GPI lipid anchor modification of proteins in kingdoms of life: analysis of protein sequence data from complete genomes
Protein Eng. Des. Sel., January 1, 2001; 14(1): 17 - 25.
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M. Frisardi, S. K. Ghosh, J. Field, K. Van Dellen, R. Rogers, P. Robbins, and J. Samuelson
The Most Abundant Glycoprotein of Amebic Cyst Walls (Jacob) Is a Lectin with Five Cys-Rich, Chitin-Binding Domains
Infect. Immun., July 1, 2000; 68(7): 4217 - 4224.
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D. P. Widney, Y.-R. Xia, A. J. Lusis, and J. B. Smith
The Murine Chemokine CXCL11 (IFN-Inducible T Cell {alpha} Chemoattractant) Is an IFN-{gamma}- and Lipopolysaccharide- Inducible Glucocorticoid-Attenuated Response Gene Expressed in Lung and Other Tissues During Endotoxemia
J. Immunol., June 15, 2000; 164(12): 6322 - 6331.
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Genome ResHome page
P. Bork
Powers and Pitfalls in Sequence Analysis: The 70% Hurdle
Genome Res., April 1, 2000; 10(4): 398 - 400.
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J.-M. Revest, L. DeMoerlooze, and C. Dickson
Fibroblast Growth Factor 9 Secretion Is Mediated by a Non-cleaved Amino-terminal Signal Sequence
J. Biol. Chem., March 10, 2000; 275(11): 8083 - 8090.
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Purified Group X Secretory Phospholipase A2 Induced Prominent Release of Arachidonic Acid from Human Myeloid Leukemia Cells
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N. Xu and B. Dahlback
A Novel Human Apolipoprotein (apoM)
J. Biol. Chem., October 29, 1999; 274(44): 31286 - 31290.
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J. D. H. Jongbloed, U. Martin, H. Antelmann, M. Hecker, H. Tjalsma, G. Venema, S. Bron, J. M. van Dijl, and J. Muller
TatC Is a Specificity Determinant for Protein Secretion via the Twin-arginine Translocation Pathway
J. Biol. Chem., December 22, 2000; 275(52): 41350 - 41357.
[Abstract] [Full Text] [PDF]



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