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. 2014 Dec 5;4:7331.
doi: 10.1038/srep07331.

Systematic Analysis of the in Situ Crosstalk of Tyrosine Modifications Reveals No Additional Natural Selection on Multiply Modified Residues

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Free PMC article

Systematic Analysis of the in Situ Crosstalk of Tyrosine Modifications Reveals No Additional Natural Selection on Multiply Modified Residues

Zhicheng Pan et al. Sci Rep. .
Free PMC article

Abstract

Recent studies have indicated that different post-translational modifications (PTMs) synergistically orchestrate specific biological processes by crosstalks. However, the preference of the crosstalk among different PTMs and the evolutionary constraint on the PTM crosstalk need further dissections. In this study, the in situ crosstalk at the same positions among three tyrosine PTMs including sulfation, nitration and phosphorylation were systematically analyzed. The experimentally identified sulfation, nitration and phosphorylation sites were collected and integrated with reliable predictions to perform large-scale analyses of in situ crosstalks. From the results, we observed that the in situ crosstalk between sulfation and nitration is significantly under-represented, whereas both sulfation and nitration prefer to co-occupy with phosphorylation at same tyrosines. Further analyses suggested that sulfation and nitration preferentially co-occur with phosphorylation at specific positions in proteins, and participate in distinct biological processes and functions. More interestingly, the long-term evolutionary analysis indicated that multi-PTM targeting tyrosines didn't show any higher conservation than singly modified ones. Also, the analysis of human genetic variations demonstrated that there is no additional functional constraint on inherited disease, cancer or rare mutations of multiply modified tyrosines. Taken together, our systematic analyses provided a better understanding of the in situ crosstalk among PTMs.

Figures

Figure 1
Figure 1. The examples for different types of PTM crosstalks.
(a) Cis-crosstalk, phosphorylation at S303 of HSF1 promotes its K298 sumoylation. (b) Trans-crosstalk between ubiquitination of SGK1 by Rictor/Cullin-1/Rbx1 and phosphorylation of Rictor by SGK1. (c) In situ crosstalk, protein PER2 is competitively O-GlcNAcylated and phosphorylated at S662. (d) A complex crosstalk among PKCδ, Caspase-3, and p53 that different types of PTM crosstalks can simultaneously occur and regulate biological functions.
Figure 2
Figure 2. The development of GPS-TSP 1.0.
(a) The sequence logo of sulfation sites. (b) The snapshot of GPS-TSP with the example of human C3a complement anaphylatoxin chemotactic receptor (C3aR, Q16581). (c) The ROC curves and AROC values for the LOO validation and 4-, 6-, 8-, 10-fold cross-validations.
Figure 3
Figure 3. Statistical analyses of GO annotations for sulfated and nitrated proteins.
The enriched GO terms for sulfated proteins (a) or nitrated proteins (b) in comparison with proteome. (c) Comparison of GO terms between sulfated and nitrated proteins. E-ratio, enrichment ratio.
Figure 4
Figure 4. Statistical analyses of GO and KEGG annotations for proteins with in situ crosstalk between sulfation or nitration and phosphorylation.
The enriched GO terms for proteins with in situ crosstalk between sulfation (a) or nitration (b) and phosphorylation in comparison with phosphorylated proteins. The enriched KEGG annotations for proteins with in situ crosstalk between sulfation (c) or nitration (d) and phosphorylation in comparison with phosphorylated proteins.
Figure 5
Figure 5. The sequence and structure preferences of known or predicted tyrosine modification sites.
Sulfation, Nitration, and Phosphorylation denote known modified tyrosines. Pre. Sulf., predicted sulfation sites in phosphorylated proteins; Pre. Nit., predicted nitration sites in phosphorylated proteins; Sulf.-Phos., in situ crosstalk of sulfation and phosphorylation in phosphorylated proteins; Nit.-Phos., in situ crosstalk of nitration and phosphorylation in phosphorylated proteins. (a) Position distribution of modified tyrosines in N-terminal, Middle, or C-terminal regions in protein sequences. (b) Distribution of modified tyrosines in a-helix, β-Strand, Coil of the secondary structure. (c) Distribution of tyrosine modification residues in exposed and buried regions. (d) Distribution of modified tyrosines in disordered and ordered regions.
Figure 6
Figure 6. The computational procedure for analyzing the long-term evolution of tyrosines.
(a) Proteome sets of eight vertebrates were obtained from the UniProt database. (b) The orthologs were pairwisely detected, and the multiple sequence alignment was performed by Clustal Omega. (c) The RCSY is calculated by the number of tyrosines appearing in the column of multi-alignment of orthologs where the species with the MBL containing the tyrosine residues. (d) The conservation levels of different types of modified or unmodified tyrosines. The lines with dots represent the enrichment ratio between the two datasets. Total, total tyrosines.

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