Dataset Information

Sequence- and Structure-Based Analysis of Tissue-Specific Phosphorylation Sites.

ABSTRACT: Phosphorylation is the most widespread and well studied reversible posttranslational modification. Discovering tissue-specific preferences of phosphorylation sites is important as phosphorylation plays a role in regulating almost every cellular activity and disease state. Here we present a comprehensive analysis of global and tissue-specific sequence and structure properties of phosphorylation sites utilizing recent proteomics data. We identified tissue-specific motifs in both sequence and spatial environments of phosphorylation sites. Target site preferences of kinases across tissues indicate that, while many kinases mediate phosphorylation in all tissues, there are also kinases that exhibit more tissue-specific preferences which, notably, are not caused by tissue-specific kinase expression. We also demonstrate that many metabolic pathways are differentially regulated by phosphorylation in different tissues.

SUBMITTER: Karabulut NP

PROVIDER: S-EPMC4917084 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Sequence- and Structure-Based Analysis of Tissue-Specific Phosphorylation Sites.

Karabulut Nermin Pinar NP Frishman Dmitrij D

PloS one 20160622 6

Phosphorylation is the most widespread and well studied reversible posttranslational modification. Discovering tissue-specific preferences of phosphorylation sites is important as phosphorylation plays a role in regulating almost every cellular activity and disease state. Here we present a comprehensive analysis of global and tissue-specific sequence and structure properties of phosphorylation sites utilizing recent proteomics data. We identified tissue-specific motifs in both sequence and spati ...[more]

PMID: 27332813

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Project description:BackgroundRyanodine receptor (RyR), a calcium-release channel located in the sarcoplasmic reticulum membrane of muscles, is the target of insecticides used against a wide range of agricultural pests. Mammalian RyRs have been shown to be under the regulatory control of several kinases and phosphatases, but little is known about the regulation of insect RyRs by phosphorylation.ResultsHere we present the crystal structures of wild-type and phospho-mimetic RyR Repeat34 domain containing PKA phosphorylation sites from diamondback moth (DBM), a major lepidopteran pest of cruciferous vegetables. The structure has unique features, not seen in mammalian RyRs, including an additional α-helix near the phosphorylation loop. Using tandem mass spectrometry, we identify several PKA sites clustering in the phosphorylation loop and the newly identified α-helix. Bioinformatics analysis shows that this α-helix is only present in Lepidoptera, suggesting an insect-specific regulation. Interestingly, the specific phosphorylation pattern is temperature-dependent. The thermal stability of the DBM Repeat34 domain is significantly lower than that of the analogous domain in the three mammalian RyR isoforms, indicating a more dynamic domain structure that can be partially unfolded to facilitate the temperature-dependent phosphorylation. Docking the structure into the cryo-electron microscopy model of full-length RyR reveals that the interface between the Repeat34 and neighboring HD1 domain is more conserved than that of the phosphorylation loop region that might be involved in the interaction with SPRY3 domain. We also identify an insect-specific glycerol-binding pocket that could be potentially targeted by novel insecticides to fight the current resistance crisis.ConclusionsThe crystal structures of the DBM Repeat34 domain reveals insect-specific temperature-dependent phosphorylation sites that may regulate insect ryanodine receptor function. It also reveals insect-specific structural features and a potential ligand-binding site that could be targeted in an effort to develop green pesticides with high species-specificity.

Project description:BackgroundPost-translational modification (PTM) is a biological process that alters proteins and is therefore involved in the regulation of various cellular activities and pathogenesis. Protein phosphorylation is an essential process and one of the most-studied PTMs: it occurs when a phosphate group is added to serine (Ser, S), threonine (Thr, T), or tyrosine (Tyr, Y) residue. Dysregulation of protein phosphorylation can lead to various diseases-most commonly neurological disorders, Alzheimer's disease, and Parkinson's disease-thus necessitating the prediction of S/T/Y residues that can be phosphorylated in an uncharacterized amino acid sequence. Despite a surplus of sequencing data, current experimental methods of PTM prediction are time-consuming, costly, and error-prone, so a number of computational methods have been proposed to replace them. However, phosphorylation prediction remains limited, owing to substrate specificity, performance, and the diversity of its features.MethodsIn the present study we propose machine-learning-based predictors that use the physicochemical, sequence, structural, and functional information of proteins to classify S/T/Y phosphorylation sites. Rigorous feature selection, the minimum redundancy/maximum relevance approach, and the symmetrical uncertainty method were employed to extract the most informative features to train the models.ResultsThe RF and SVM models generated using diverse feature types in the present study were highly accurate as is evident from good values for different statistical measures. Moreover, independent test sets and benchmark validations indicated that the proposed method clearly outperformed the existing methods, demonstrating its ability to accurately predict protein phosphorylation.ConclusionsThe results obtained in the present work indicate that the proposed computational methodology can be effectively used for predicting putative phosphorylation sites further facilitating discovery of various biological processes mechanisms.

Dataset Information

Sequence- and Structure-Based Analysis of Tissue-Specific Phosphorylation Sites.

Publications

Sequence- and Structure-Based Analysis of Tissue-Specific Phosphorylation Sites.

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