Clustering of phosphorylation site recognition motifs can be exploited to predict the targets of cyclin-dependent kinase. Genome Biol 8:R23

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
Genome biology (Impact Factor: 10.81). 02/2007; 8(2):R23. DOI: 10.1186/gb-2007-8-2-r23
Source: PubMed


Protein kinases are critical to cellular signalling and post-translational gene regulation, but their biological substrates are difficult to identify. We show that cyclin-dependent kinase (CDK) consensus motifs are frequently clustered in CDK substrate proteins. Based on this, we introduce a new computational strategy to predict the targets of CDKs and use it to identify new biologically interesting candidates. Our data suggest that regulatory modules may exist in protein sequence as clusters of short sequence motifs.

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    • "The turnover of phosphorylation sites found in clusters of sites is an appealing hypothesis to explain at least a fraction of rapidly evolving phosphorylation sites (Landry et al., 2009). Indeed, a large fraction of phosphorylation sites are overrepresented in disordered regions of proteins where they occur in clusters of several juxtaposed sites (Moses et al., 2007a; Landry et al., 2009; Schweiger and Linial, 2010) and could act as groups rather than individual sites as described in Section “Molecular Mechanisms of Protein Regulation by Phosphorylation”(Figure 1). Sites could be gained and lost within a given region with limited effect on the overall function, but contributing to an increased rate of evolution if one considers sites individually. "
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    ABSTRACT: Most proteins are regulated by posttranslational modifications and changes in these modifications contribute to evolutionary changes as well as to human diseases. Phosphorylation of serines, threonines, and tyrosines are the most common modifications identified to date in eukaryotic proteomes. While the mode of action and the function of most phosphorylation sites remain unknown, functional studies have shown that phosphorylation affects protein stability, localization and ability to interact. Two broad modes of action have been described for protein phosphorylation. The first mode corresponds to the canonical and qualitative view whereby single phosphorylation sites act as molecular switches that either turn on or off specific protein functions through direct or allosteric effects. The second mode is more akin to a rheostat than a switch. In this case, a group of phosphorylation sites in a given protein region contributes collectively to the modification of the protein, irrespective of the precise position of individual sites, through an aggregate property. Here we discuss these two types of regulation and examine how they affect the rate and patterns of protein phosphorylation evolution. We describe how the evolution of clusters of phosphorylation sites can be studied under the framework of complex traits evolution and stabilizing selection.
    Frontiers in Genetics 07/2014; 5:245. DOI:10.3389/fgene.2014.00245
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    • "These searches produced just over 60 hits, of which 13 were previously reported Cdc14 substrates. To identify substrates, we first focused on proteins with clusters of optimal Cdc14 sites because regulatory Cdk phosphorylation commonly occurs in clusters on disordered loops (Holt et al., 2009; Moses et al., 2007). Yen1 caught our eye because it contains more optimal Cdc14 sites than any other yeast protein (Table S3). "
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    ABSTRACT: Faithful genome transmission during cell division requires precise, coordinated action of DNA metabolic enzymes, including proteins responsible for DNA damage detection and repair. Dynamic phosphorylation plays an important role in controlling repair enzymes during the DNA damage response (DDR). Cdc14 phosphatases oppose cyclin-dependent kinase (Cdk) phosphorylation and have been implicated in the DDR in several model systems. Here, we have refined the substrate specificity of budding yeast Cdc14 and, using this insight, identified the Holliday junction resolvase Yen1 as a DNA repair target of Cdc14. Cdc14 activation at anaphase triggers nuclear accumulation and enzymatic activation of Yen1, likely to resolve persistent recombinational repair intermediates. Consistent with this, expression of a phosphomimetic Yen1 mutant increased sister chromatid nondisjunction. In contrast, lack of Cdk phosphorylation resulted in constitutive activity and elevated crossover-associated repair. The precise timing of Yen1 activation, governed by core cell-cycle regulators, helps coordinate DNA repair with chromosome segregation and safeguards against genome destabilization.
    Molecular cell 03/2014; 54(1). DOI:10.1016/j.molcel.2014.02.012 · 14.02 Impact Factor
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    • "This could be the case if the role of the modifications were to regulate the bulk electrostatics of a protein region (Strickfaden et al, 2007) or to achieve a non-linear regulatory outcome (K~ oivom€ agi et al, 2011). Phosphosites are often found in clusters within proteins (Schweiger & Linial, 2010; Christian et al, 2012) and the clustering of sites matching a kinase motif can serve as a predictor for kinase-target interactions further highlighting the functional importance of these clusters (Moses et al, 2007a). In addition, there are well-characterized examples where even the regulation of a crucial process like DNA re-replication is conserved but implemented via different regulatory phosphorylation sites (Moses et al, 2007b; Drury & Diffley, 2009). "
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    ABSTRACT: Protein post-translational modifications (PTMs) allow the cell to regulate protein activity and play a crucial role in the response to changes in external conditions or internal states. Advances in mass spectrometry now enable proteome wide characterization of PTMs and have revealed a broad functional role for a range of different types of modifications. Here we review advances in the study of the evolution and function of PTMs that were spurred by these technological improvements. We provide an overview of studies focusing on the origin and evolution of regulatory enzymes as well as the evolutionary dynamics of modification sites. Finally, we discuss different mechanisms of altering protein activity via post-translational regulation and progress made in the large-scale functional characterization of PTM function.
    Molecular Systems Biology 12/2013; 9(1):714. DOI:10.1002/msb.201304521 · 10.87 Impact Factor
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