Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 34, Pages 14091-14096Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1102835108
Keywords
aminoacyl-tRNA synthetase; morphogenesis; mitogen-activated protein kinase pathway; Ras1; X-ray crystallography
Categories
Funding
- Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/SAU-MII/70634/2006, PTDC/BIA-BCM/64745/2006, PTDC/SAU-GMG/098850/2008, PTDC/BIA-MIC/099826/2008, REEQ/564/BIO/2005]
- EU-FEDER
- FCT [BD/15233/2004]
- University of Coimbra
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-MIC/099826/2008, PTDC/SAU-GMG/098850/2008, PTDC/BIA-BCM/64745/2006, PD/BD/135485/2018, PTDC/SAU-MII/70634/2006] Funding Source: FCT
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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.
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