Robustness by intrinsically disordered C-termini and translational readthrough

Abstract

During protein synthesis genetic instructions are passed from DNA via mRNA to the ribosome to assemble a protein chain. Occasionally, stop codons in the mRNA are bypassed and translation continues into the untranslated region (3′-UTR). This process, called translational readthrough (TR), yields a protein chain that becomes longer than would be predicted from the DNA sequence alone. Protein sequences vary in propensity for translational errors, which may yield evolutionary constraints by limiting evolutionary paths. Here we investigated TR in Saccharomyces cerevisiae by analysing ribosome profiling data. We clustered proteins as either prone or non-prone to TR, and conducted comparative analyses. We find that a relatively high frequency (5%) of genes undergo TR, including ribosomal subunit proteins. Our main finding is that proteins undergoing TR are highly expressed and have a higher proportion of intrinsically disordered C-termini. We suggest that highly expressed proteins may compensate for the deleterious effects of TR by having intrinsically disordered C-termini, which may provide conformational flexibility but without distorting native function. Moreover, we discuss whether minimizing deleterious effects of TR is also enabling exploration of the phenotypic landscape of protein isoforms.

Stop-codon read-through arises largely from molecular errors and is generally nonadaptive

“…Indeed, the rate of stop-codon read-through is negatively correlated with the gene expression level in both the yeast (Spearman’s ρ = -0.49, P = 0.01; Fig 1A ) and fruit fly ( ρ = -0.45, P < 10 −14 ; Fig 1B ). The yeast result confirms that from a recent, independent ribosome-profiling experiment [23]. Note that because the rate of read-through is computed using ribosome profiling data while the gene expression level is computed using mRNA sequencing data, the above correlation is not an artifact of statistical non-independence that has been found to affect a number of gene expression analyses [24].…”

Stochastic Gain and Loss of Novel Transcribed Open Reading Frames in the Human Lineage

“…2017 ). ISD has also been shown to impact the emergence of novel protein extensions in yeast ( Kleppe and Bornberg-Bauer 2018 ). However, studies of yeast transcriptomes showed that younger ORFs have lower rather than higher levels of disorder than older ORFs ( Carvunis et al.…”

De novo gene birth

“…Novel C-terminal domains may first evolve under weak selection via occasional expression through read-through translation, as in the preadaptation model, only later becoming constitutively expressed through a mutation that disrupts the stop codon [126, 129]. Genes experiencing high translational readthrough tend to have intrinsically disordered C-termini [130]. Furthermore, existing genes are often close to repetitive sequences that encode disordered domains.…”