Testing whether metazoan tyrosine loss was driven by selection against promiscuous phosphorylation

Area of Science:

• Evolutionary biology
• Molecular biology
• Biochemistry

Background:

• Protein tyrosine phosphorylation is a crucial regulatory mechanism in multicellular organisms (metazoans).
• Kinase enzyme diversity has increased, coinciding with a genome-wide decrease in protein tyrosine content.
• A recent hypothesis suggests this tyrosine reduction was driven by selection to prevent potentially harmful promiscuous phosphorylation.

Purpose of the Study:

• To test the hypothesis that selection against deleterious phosphorylation drove tyrosine loss in metazoans.
• To evaluate if selection strength correlates with phosphorylation likelihood (solvent accessibility, disorder) and protein abundance.
• To determine if selection favors removal over creation of tyrosine residues.

Main Methods:

• Comparative analysis of tyrosine distributions in human and yeast orthologous proteins.
• Examination of human population genomic variation data to assess selection against tyrosine mutations.
• Statistical evaluation of selection pressures on tyrosine residues based on predicted phosphorylation potential and protein abundance.

Main Results:

• The predicted effects of selection against promiscuous phosphorylation on tyrosine were modest.
• Selection strength did not strongly correlate with residue accessibility, disorder, or protein abundance as predicted.
• Selection against creating tyrosine was only slightly stronger than against removing it, and modest overall.

Conclusions:

• Selection against deleterious protein tyrosine phosphorylation was not the dominant force driving tyrosine loss in metazoans.
• Other evolutionary pressures likely played a more significant role in the reduction of tyrosine content.
• The hypothesis that avoidance of promiscuous phosphorylation primarily drove tyrosine loss is not strongly supported by the data.