title: Unveiling the structural basis for translational ambiguity tolerance in a human fungal pathogen.
abstract: In a restricted group of opportunistic fungal pathogens the universal leucine CUG codon is translated both as serine (97%) and leucine (3%), challenging the concept that translational ambiguity has a negative impact in living organisms. To elucidate the molecular mechanisms underlying the in vivo tolerance to a nonconserved genetic code alteration, we have undertaken an extensive structural analysis of proteins containing CUG-encoded residues and solved the crystal structures of the two natural isoforms of Candida albicans seryl-tRNA synthetase. We show that codon reassignment resulted in a nonrandom genome-wide CUG redistribution tailored to minimize protein misfolding events induced by the large-scale leucine-to-serine replacement within the CTG clade. Leucine or serine incorporation at the CUG position in C. albicans seryl-tRNA synthetase induces only local structural changes and, although both isoforms display tRNA serylation activity, the leucine-containing isoform is more active. Similarly, codon ambiguity is predicted to shape the function of C. albicans proteins containing CUG-encoded residues in functionally relevant positions, some of which have a key role in signaling cascades associated with morphological changes and pathogenesis. This study provides a first detailed analysis on natural reassignment of codon identity, unveiling a highly dynamic evolutionary pattern of thousands of fungal CUG codons to confer an optimized balance between protein structural robustness and functional plasticity.
authors.affiliation: Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Rocha
authors.forename: Pedro José Barbosa
authors.initials: PJ
authors.lastname: Pereira
authors.forename: Manuel A S
authors.initials: MA
authors.lastname: Santos
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
mesh_terms: D000596:Amino Acids; D002176:Candida albicans / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D003062:Codon / Q000235:genetics; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008958:Models, Molecular; D016366:Open Reading Frames / Q000235:genetics; D014176:Protein Biosynthesis; D017510:Protein Folding; D055503:Protein Multimerization; D012714:Serine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D003062:Codon; D005656:Fungal Proteins; D007527:Isoenzymes; D012714:Serine-tRNA Ligase