A Mechanism for the Evolution of Phosphorylation Sites

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell (Impact Factor: 32.24). 11/2011; 147(4):934-46. DOI: 10.1016/j.cell.2011.08.052
Source: PubMed

ABSTRACT Protein phosphorylation provides a mechanism for the rapid, reversible control of protein function. Phosphorylation adds negative charge to amino acid side chains, and negatively charged amino acids (Asp/Glu) can sometimes mimic the phosphorylated state of a protein. Using a comparative genomics approach, we show that nature also employs this trick in reverse by evolving serine, threonine, and tyrosine phosphorylation sites from Asp/Glu residues. Structures of three proteins where phosphosites evolved from acidic residues (DNA topoisomerase II, enolase, and C-Raf) show that the relevant acidic residues are present in salt bridges with conserved basic residues, and that phosphorylation has the potential to conditionally restore the salt bridges. The evolution of phosphorylation sites from glutamate and aspartate provides a rationale for why phosphorylation sometimes activates proteins, and helps explain the origins of this important and complex process.

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Available from: Samuel Mark Pearlman, Nov 19, 2014
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    • "Cell Systems 1, August 26, 2015 ª2015 Elsevier Inc. 111 Cell Systems Perspective is reflected in the observation of pervasive rewiring in kinase and transcription factor interactions (Baker et al., 2012; Pearlman et al., 2011), at a faster rate than in metabolic and PPI networks (Shou et al., 2011). It might be expected that in these networks pervasive edge changes would lower the likelihood of modular gene loss occurring under selective pressure or following duplication events, leading to a depletion of signaling and transcriptional regulators from sets of correlated phylogenetic profiles. "
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    • "Some amino‐acids can sometimes mimic PTMs but few studies have taken this into account in comparative analysis. For example, the negatively charged Asp/Glu can often mimic phospho‐Ser/Thr and analysis of sequence alignments of highly conserved proteins suggest that on the order of 5% of phosphosites occur in positions that likely were Asp/Glu in the ancestral state (Pearlman et al, 2011). These positions may highlight phosphosites that positively regulate proteins by conditionally restoring the negative charges present in the ancestral states (Pearlman et al, 2011). "
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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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    • "The authors demonstrated this principle on the example of phosphorylatable serine, threonine, and tyrosine residues in Topo II, enolase, and Raf protein structures, respectively. These phospho-residues have the capacity to form stabilizing salt bridges formed by glutamate and aspartate residues in the ancestral versions of the proteins (Pearlman et al., 2011). This evolutionary principle is of course not universal for all phosphorylation sites, especially not for those where phosphorylation inactivates the proteins. "
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    ABSTRACT: In this review we address some recent developments in the field of bacterial protein phosphorylation, focusing specifically on serine/threonine and tyrosine kinases. We present an overview of recent studies outlining the scope of physiological processes that are regulated by phosphorylation, ranging from cell cycle, growth, cell morphology, to metabolism, developmental phenomena and virulence. Specific emphasis is placed on Mycobacterium tuberculosis as a showcase organism for serine/threonine kinases, and Bacillus subtilis to illustrate the importance of protein phosphorylation in developmental processes. We argue that bacterial serine/threonine and tyrosine kinases have a distinctive feature of phosphorylating multiple substrates, and might thus represent integration nodes in the signaling network. Some open questions regarding the evolutionary benefits of relaxed substrate selectivity of these kinases are treated, as well as the notion of non-functional "background" phosphorylation of cellular proteins. We also argue that phosphorylation events for which an immediate regulatory effect is not clearly established should not be dismissed as unimportant, as they may have a role in cross-talk with other post-translational modifications. Finally, recently developed methods for studying protein phosphorylation networks in bacteria are briefly discussed. This article is protected by copyright. All rights reserved.
    FEMS Microbiology Letters 06/2013; 346(1). DOI:10.1111/1574-6968.12189 · 2.12 Impact Factor
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