GC-made protein disorder sheds new light on vertebrate evolution

• GC-transition is found to increase protein intrinsic disorder content in endothermic, but not in ectothermic vertebrates.
• GC transition promotes disordered residues along with increase of protein hydrophobicity.
• This disorder content enrichment is found to promote protein functional diversity.
• Higher disorder content is also found to minimize the protein-aggregation propensity.

At the emergence of endothermic vertebrates, GC rich regions of the ectothermic ancestral genomes underwent a significant GC increase. Such an increase was previously postulated to increase thermodynamic and structural stability of proteins through selective increase of protein hydrophobicity. Here, we found that, increase in GC content promotes a higher content of disorder promoting amino acid in endothermic vertebrates proteins and that the increase in hydrophobicity is mainly due to a higher content of the small disorder promoting amino acid alanine. In endothermic vertebrates, prevalence of disordered residues was found to promote functional diversity of proteins encoded by GC rich genes. Higher fraction of disordered residues in this group of proteins was also found to minimize their aggregation tendency. Thus, we propose that the GC transition has favored disordered residues to promote functional diversity in GC rich genes, and to protect them against functional loss by protein misfolding.