Predicting the Structural Effects of CUG Codon Translation on Uncharacterized Proteins in Candida albicans

In the standard genetic code, the CUG triplet is translated as leucine. The pathogenic yeast Candida albicans and other CTG-clade yeasts contain tRNA_CAG, which is recognized by both leucine- and serine-tRNA synthetases. The CUG codon in these yeasts is translated most often as serine, and only in 3-5% of cases as leucine. Therefore, CTG Candida species have unstable proteomes. The effect of serine-leucine exchange on the structure and function of proteins has only been experimentally examined for a few cases. In C. albicans, CUG codons occur even in genes deemed to be essential. This means that serine-leucine ambiguity either does not affect the structure and function of the respective proteins, or that the presence of these amino acids at specific positions is associated with meaningful alteration of the proteins' function. This study employed AlphaFold2 to evaluate the potential effects of serine-to-leucine exchange in 12 proteins encoded by essential genes lacking orthologs in other yeasts and human genomes. The low homology with known proteins allowed us to make only low-confidence predictions. The analyzed proteins could be grouped into subsets based on the structural outcomes. Structural changes were observed only in four proteins. The remaining eight proteins showed no significant differences between serine and leucine variants.