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      Functional Divergence and Evolutionary Turnover in Mammalian Phosphoproteomes

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Protein phosphorylation is a key mechanism to regulate protein functions. However, the contribution of this protein modification to species divergence is still largely unknown. Here, we studied the evolution of mammalian phosphoregulation by comparing the human and mouse phosphoproteomes. We found that 84% of the positions that are phosphorylated in one species or the other are conserved at the residue level. Twenty percent of these conserved sites are phosphorylated in both species. This proportion is 2.5 times more than expected by chance alone, suggesting that purifying selection is preserving phosphoregulation. However, we show that the majority of the sites that are conserved at the residue level are differentially phosphorylated between species. These sites likely result from false-negative identifications due to incomplete experimental coverage, false-positive identifications and non-functional sites. In addition, our results suggest that at least 5% of them are likely to be true differentially phosphorylated sites and may thus contribute to the divergence in phosphorylation networks between mouse and humans and this, despite residue conservation between orthologous proteins. We also showed that evolutionary turnover of phosphosites at adjacent positions (in a distance range of up to 40 amino acids) in human or mouse leads to an over estimation of the divergence in phosphoregulation between these two species. These sites tend to be phosphorylated by the same kinases, supporting the hypothesis that they are functionally redundant. Our results support the hypothesis that the evolutionary turnover of phosphorylation sites contributes to the divergence in phosphorylation profiles while preserving phosphoregulation. Overall, our study provides advanced analyses of mammalian phosphoproteomes and a framework for the study of their contribution to phenotypic evolution.

          Author Summary

          Understanding how differences in cellular regulation lead to phenotypic differences between species remains an open challenge in evolutionary genetics. The extensive phosphorylation data currently available allows to compare the human and mouse phosphoproteomes and to measure changes in their phosphoregulation. We found a general conservation of phosphorylation sites between these two species. However, a fraction of sites are conserved at the sequence level (the same amino acid is present in both species) but differ in their phosphorylation status. These sites represent candidate sites that have the potential to explain differences between human and mouse signalling networks that do not depend on the divergence of orthologous residues. Furthermore, we identified several sites where to a phosphorylation site in one species corresponds a non-phosphorylatable residue in the other one. These cases represent clear differences in protein regulation. Recent studies suggest that phosphorylation sites can shift position during evolution, leading to configurations in which pairs of divergent phosphorylation sites are functionally redundant. We identified more than 100 putative such cases, suggesting that divergence in amino acid does not necessarily imply functional divergence when comparing phosphoproteomes. Overall, our study provides new key concepts and data for the study of how regulatory differences may be linked to phenotypic ones at the network level.

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          Most cited references 45

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          Systematic and quantitative assessment of the ubiquitin-modified proteome.

          Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the human ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly)-containing isopeptides following trypsin digestion. We identify ~19,000 diGly-modified lysine residues within ~5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition, indicating both a dependence on ongoing translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse

            PhosphoSitePlus (http://www.phosphosite.org) is an open, comprehensive, manually curated and interactive resource for studying experimentally observed post-translational modifications, primarily of human and mouse proteins. It encompasses 1 30 000 non-redundant modification sites, primarily phosphorylation, ubiquitinylation and acetylation. The interface is designed for clarity and ease of navigation. From the home page, users can launch simple or complex searches and browse high-throughput data sets by disease, tissue or cell line. Searches can be restricted by specific treatments, protein types, domains, cellular components, disease, cell types, cell lines, tissue and sequences or motifs. A few clicks of the mouse will take users to substrate pages or protein pages with sites, sequences, domain diagrams and molecular visualization of side-chains known to be modified; to site pages with information about how the modified site relates to the functions of specific proteins and cellular processes and to curated information pages summarizing the details from one record. PyMOL and Chimera scripts that colorize reactive groups on residues that are modified can be downloaded. Features designed to facilitate proteomic analyses include downloads of modification sites, kinase–substrate data sets, sequence logo generators, a Cytoscape plugin and BioPAX download to enable pathway visualization of the kinase–substrate interactions in PhosphoSitePlus®.
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              Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution.

              To explore the mechanisms and evolution of cell-cycle control, we analyzed the position and conservation of large numbers of phosphorylation sites for the cyclin-dependent kinase Cdk1 in the budding yeast Saccharomyces cerevisiae. We combined specific chemical inhibition of Cdk1 with quantitative mass spectrometry to identify the positions of 547 phosphorylation sites on 308 Cdk1 substrates in vivo. Comparisons of these substrates with orthologs throughout the ascomycete lineage revealed that the position of most phosphorylation sites is not conserved in evolution; instead, clusters of sites shift position in rapidly evolving disordered regions. We propose that the regulation of protein function by phosphorylation often depends on simple nonspecific mechanisms that disrupt or enhance protein-protein interactions. The gain or loss of phosphorylation sites in rapidly evolving regions could facilitate the evolution of kinase-signaling circuits.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                January 2014
                January 2014
                23 January 2014
                : 10
                : 1
                Affiliations
                [1 ]Département de Biologie, Université Laval, Québec, Canada
                [2 ]Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Canada
                [3 ]PROTEO, The Quebec Research Network on Protein Function, Structure and Engineering, Université Laval, Québec, Canada
                National Institute of Genetics, Japan
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CRL LF. Performed the experiments: LF. Analyzed the data: LF. Contributed reagents/materials/analysis tools: MO. Wrote the paper: LF CRL.

                Article
                PGENETICS-D-13-01638
                10.1371/journal.pgen.1004062
                3900387

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                Funding
                This work was supported by Canadian Institutes of Health Research (CIHR)(GMX-191597). CRL is a CIHR New Investigator. LF was supported by a fellowship from the Fonds de Recherche du Québec - Nature et Technologies (FRQ-NT) and LF and MO by the Quebec Research Network on Protein Function, Structure and Engineering (PROTEO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Computational Biology
                Genomics
                Comparative Genomics
                Molecular Genetics
                Gene Regulation
                Population Genetics
                Natural Selection
                Regulatory Networks
                Sequence Analysis
                Signaling Networks
                Systems Biology
                Evolutionary Biology
                Population Genetics
                Natural Selection
                Comparative Genomics
                Evolutionary Genetics
                Genomic Evolution
                Genomics
                Comparative Genomics
                Systems Biology

                Genetics

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