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


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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    • "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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    • "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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