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Title: Unveiling the structural basis for translational ambiguity tolerance in a human fungal pathogen
Author: Rocha, Rita
Pereira, Pedro José Barbosa
Santos, Manuel A. S.
Macedo-Ribeiro, Sandra
Keywords: Aminoacyl-tRNA synthetase
Mitogen-activated protein kinase
Ras1X-ray crystallography
Issue Date: 23-Aug-2011
Publisher: National Academy of Sciences
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.
Peer review: yes
DOI: 10.1073/pnas.1102835108
ISSN: 0027-8424
Appears in Collections:CESAM - Artigos
DBio - Artigos

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