Disulfide bonds enable accelerated protein evolution

Abstract

The different proteins of any proteome evolve at enormously different rates. What factors contribute to this variability, and to what extent, is still a largely open question. We hypothesized that disulfide bonds, by increasing protein stability, should make proteins' structures relatively independent of their amino acid sequences, thus acting as buffers of deleterious mutations and enabling accelerated sequence evolution. In agreement with this hypothesis, we observed that membrane proteins with disulfide bonds evolved 88% faster than those without disulfide bonds, and that extracellular proteins with disulfide bonds evolved 49% faster than those without disulfide bonds. In addition, genes encoding proteins with disulfide bonds exhibit an increased likelihood of showing signatures of positive selection. Multivariate analyses indicate that the trend is independent of a number of potentially confounding factors. The effect, however, is not observed among the longest proteins, which can become stabilized by mechanisms other than disulfide bonds.