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Computational prediction of secreted proteins in gram-negative bacteria.

ABSTRACT: Gram-negative bacteria harness multiple protein secretion systems and secrete a large proportion of the proteome. Proteins can be exported to periplasmic space, integrated into membrane, transported into extracellular milieu, or translocated into cytoplasm of contacting cells. It is important for accurate, genome-wide annotation of the secreted proteins and their secretion pathways. In this review, we systematically classified the secreted proteins according to the types of secretion systems in Gram-negative bacteria, summarized the known features of these proteins, and reviewed the algorithms and tools for their prediction.

SUBMITTER: Hui X

PROVIDER: S-EPMC8047123 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Computational prediction of secreted proteins in gram-negative bacteria.

Hui Xinjie X Chen Zewei Z Zhang Junya J Lu Moyang M Cai Xuxia X Deng Yuping Y Hu Yueming Y Wang Yejun Y

Computational and structural biotechnology journal 20210322

Gram-negative bacteria harness multiple protein secretion systems and secrete a large proportion of the proteome. Proteins can be exported to periplasmic space, integrated into membrane, transported into extracellular milieu, or translocated into cytoplasm of contacting cells. It is important for accurate, genome-wide annotation of the secreted proteins and their secretion pathways. In this review, we systematically classified the secreted proteins according to the types of secretion systems in ...[more]

PMID: 33897982

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Project description:BackgroundMany pathogens use a type III secretion system to translocate virulence proteins (called effectors) in order to adapt to the host environment. To date, many prediction tools for effector identification have been developed. However, these tools are insufficiently accurate for producing a list of putative effectors that can be applied directly for labor-intensive experimental verification. This also suggests that important features of effectors have yet to be fully characterized.ResultsIn this study, we have constructed an accurate approach to predicting secreted virulence effectors from Gram-negative bacteria. This consists of a support vector machine-based discriminant analysis followed by a simple criteria-based filtering. The accuracy was assessed by estimating the average number of true positives in the top-20 ranking in the genome-wide screening. In the validation, 10 sets of 20 training and 20 testing examples were randomly selected from 40 known effectors of Salmonella enterica serovar Typhimurium LT2. On average, the SVM portion of our system predicted 9.7 true positives from 20 testing examples in the top-20 of the prediction. Removal of the N-terminal instability, codon adaptation index and ProtParam indices decreased the score to 7.6, 8.9 and 7.9, respectively. These discrimination features suggested that the following characteristics of effectors had been uncovered: unstable N-terminus, non-optimal codon usage, hydrophilic, and less aliphathic. The secondary filtering process represented by coexpression analysis and domain distribution analysis further refined the average true positive counts to 12.3. We further confirmed that our system can correctly predict known effectors of P. syringae DC3000, strongly indicating its feasibility.ConclusionsWe have successfully developed an accurate prediction system for screening effectors on a genome-wide scale. We confirmed the accuracy of our system by external validation using known effectors of Salmonella and obtained the accurate list of putative effectors of the organism. The level of accuracy was sufficient to yield candidates for gene-directed experimental verification. Furthermore, new features of effectors were revealed: non-optimal codon usage and instability of the N-terminal region. From these findings, a new working hypothesis is proposed regarding mechanisms controlling the translocation of virulence effectors and determining the substrate specificity encoded in the secretion system.

Project description:BackgroundGenome-wide prediction of protein subcellular localization is an important type of evidence used for inferring protein function. While a variety of computational tools have been developed for this purpose, errors in the gene models and use of protein sorting signals that are not recognized by the more commonly accepted tools can diminish the accuracy of their output.ResultsAs part of an effort to manually curate the annotations of 19 strains of Shewanella, numerous insights were gained regarding the use of computational tools and proteomics data to predict protein localization. Identification of the suite of secretion systems present in each strain at the start of the process made it possible to tailor-fit the subsequent localization prediction strategies to each strain for improved accuracy. Comparisons of the computational predictions among orthologous proteins revealed inconsistencies in the computational outputs, which could often be resolved by adjusting the gene models or ortholog group memberships. While proteomic data was useful for verifying start site predictions and post-translational proteolytic cleavage, care was needed to distinguish cellular versus sample processing-mediated cleavage events. Searches for lipoprotein signal peptides revealed that neither TatP nor LipoP are designed for identification of lipoprotein substrates of the twin arginine translocation system and that the +2 rule for lipoprotein sorting does not apply to this Genus. Analysis of the relationships between domain occurrence and protein localization prediction enabled identification of numerous location-informative domains which could then be used to refine or increase confidence in location predictions. This collective knowledge was used to develop a general strategy for predicting protein localization that could be adapted to other organisms.ConclusionImproved localization prediction accuracy is not simply a matter of developing better computational algorithms. It also entails gathering key knowledge regarding the host architecture and translocation machinery and associated substrate recognition via experimentation and integration of diverse computational analyses from many proteins and, where possible, that are derived from different species within the same genus.

Dataset Information

Computational prediction of secreted proteins in gram-negative bacteria.

Publications

Computational prediction of secreted proteins in gram-negative bacteria.

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