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A comprehensive assessment of N-terminal signal peptides prediction methods.

ABSTRACT: BACKGROUND: Amino-terminal signal peptides (SPs) are short regions that guide the targeting of secretory proteins to the correct subcellular compartments in the cell. They are cleaved off upon the passenger protein reaching its destination. The explosive growth in sequencing technologies has led to the deposition of vast numbers of protein sequences necessitating rapid functional annotation techniques, with subcellular localization being a key feature. Of the myriad software prediction tools developed to automate the task of assigning the SP cleavage site of these new sequences, we review here, the performance and reliability of commonly used SP prediction tools. RESULTS: The available signal peptide data has been manually curated and organized into three datasets representing eukaryotes, Gram-positive and Gram-negative bacteria. These datasets are used to evaluate thirteen prediction tools that are publicly available. SignalP (both the HMM and ANN versions) maintains consistency and achieves the best overall accuracy in all three benchmarking experiments, ranging from 0.872 to 0.914 although other prediction tools are narrowing the performance gap. CONCLUSION: The majority of the tools evaluated in this study encounter no difficulty in discriminating between secretory and non-secretory proteins. The challenge clearly remains with pinpointing the correct SP cleavage site. The composite scoring schemes employed by SignalP may help to explain its accuracy. Prediction task is divided into a number of separate steps, thus allowing each score to tackle a particular aspect of the prediction.

SUBMITTER: Choo KH

PROVIDER: S-EPMC2788353 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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A comprehensive assessment of N-terminal signal peptides prediction methods.

Choo Khar Heng KH Tan Tin Wee TW Ranganathan Shoba S

BMC bioinformatics 20091203

<h4>Background</h4>Amino-terminal signal peptides (SPs) are short regions that guide the targeting of secretory proteins to the correct subcellular compartments in the cell. They are cleaved off upon the passenger protein reaching its destination. The explosive growth in sequencing technologies has led to the deposition of vast numbers of protein sequences necessitating rapid functional annotation techniques, with subcellular localization being a key feature. Of the myriad software prediction to ...[more]

PMID: 19958512

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Project description:Secreted proteins play an important part in the pathogenicity of Mycobacterium tuberculosis, and are the primary source of vaccine and diagnostic candidates. A majority of these proteins are exported via the signal peptidase I-dependent pathway, and have a signal peptide that is cleaved off during the secretion process. Sequence similarities within signal peptides have spurred the development of several algorithms for predicting their presence as well as the respective cleavage sites. For proteins exported via this pathway, algorithms exist for eukaryotes, and for Gram-negative and Gram-positive bacteria. However, the unique structure of the mycobacterial membrane raises the question of whether the existing algorithms are suitable for predicting signal peptides within mycobacterial proteins. In this work, we have evaluated the performance of nine signal peptide prediction algorithms on a positive validation set, consisting of 57 proteins with a verified signal peptide and cleavage site, and a negative set, consisting of 61 proteins that have an N-terminal sequence that confirms the annotated translational start site. We found the hidden Markov model of SignalP v3.0 to be the best-performing algorithm for predicting the presence of a signal peptide in mycobacterial proteins. It predicted no false positives or false negatives, and predicted a correct cleavage site for 45 of the 57 proteins in the positive set. Based on these results, we used the hidden Markov model of SignalP v3.0 to analyse the 10 available annotated proteomes of mycobacterial species, including annotations of M. tuberculosis H37Rv from the Wellcome Trust Sanger Institute and the J. Craig Venter Institute (JCVI). When excluding proteins with transmembrane regions among the proteins predicted to harbour a signal peptide, we found between 7.8 and 10.5% of the proteins in the proteomes to be putative secreted proteins. Interestingly, we observed a consistent difference in the percentage of predicted proteins between the Sanger Institute and JCVI. We have determined the most valuable algorithm for predicting signal peptidase I-processed proteins of M. tuberculosis, and used this algorithm to estimate the number of mycobacterial proteins with the potential to be exported via this pathway.

Project description:MotivationPair-wise residue-residue contacts in proteins can be predicted from both threading templates and sequence-based machine learning. However, most structure modeling approaches only use the template-based contact predictions in guiding the simulations; this is partly because the sequence-based contact predictions are usually considered to be less accurate than that by threading. With the rapid progress in sequence databases and machine-learning techniques, it is necessary to have a detailed and comprehensive assessment of the contact-prediction methods in different template conditions.ResultsWe develop two methods for protein-contact predictions: SVM-SEQ is a sequence-based machine learning approach which trains a variety of sequence-derived features on contact maps; SVM-LOMETS collects consensus contact predictions from multiple threading templates. We test both methods on the same set of 554 proteins which are categorized into 'Easy', 'Medium', 'Hard' and 'Very Hard' targets based on the evolutionary and structural distance between templates and targets. For the Easy and Medium targets, SVM-LOMETS obviously outperforms SVM-SEQ; but for the Hard and Very Hard targets, the accuracy of the SVM-SEQ predictions is higher than that of SVM-LOMETS by 12-25%. If we combine the SVM-SEQ and SVM-LOMETS predictions together, the total number of correctly predicted contacts in the Hard proteins will increase by more than 60% (or 70% for the long-range contact with a sequence separation > or =24), compared with SVM-LOMETS alone. The advantage of SVM-SEQ is also shown in the CASP7 free modeling targets where the SVM-SEQ is around four times more accurate than SVM-LOMETS in the long-range contact prediction. These data demonstrate that the state-of-the-art sequence-based contact prediction has reached a level which may be helpful in assisting tertiary structure modeling for the targets which do not have close structure templates. The maximum yield should be obtained by the combination of both sequence- and template-based predictions.

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A comprehensive assessment of N-terminal signal peptides prediction methods.

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A comprehensive assessment of N-terminal signal peptides prediction methods.

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