Functional substitution of a eukaryotic glycyl-tRNA synthetase with an evolutionarily unrelated bacterial cognate enzyme.

Two oligomeric types of glycyl-tRNA synthetase (GlyRS) are found in nature: a α2 type and a α2ß2 type. The former has been identified in all three kingdoms of life and often pairs with tRNAGly that carries an A73 discriminator base, while the latter is found only in bacteria and chloroplasts and is almost always coupled with tRNAGly that contains U73. In the yeast Saccharomyces cerevisiae, a single GlyRS gene, GRS1, provides both the cytoplasmic and mitochondrial functions, and tRNAGly isoacceptors in both compartments possess A73. We showed herein that Homo sapiens and Arabidopsis thaliana cytoplasmic GlyRSs (both α2-type enzymes) can rescue both the cytoplasmic and mitochondrial defects of a yeast grs1- strain, while Escherichia coli GlyRS (a α2ß2-type enzyme) and A. thaliana organellar GlyRS (a (αß)2-type enzyme) failed to rescue either defect of the yeast mull allele. However, a head-to-tail αß fusion of E. coli GlyRS effectively supported the mitochondrial function. Our study suggests that a α2-type eukaryotic GlyRS may be functionally substituted with a α2ß2-type bacterial cognate enzyme despite their remote evolutionary relationships.

GARS axonopathy: not every neuron's cup of tRNA.

Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work.