Glycyl-tRNA Synthetase (Eukaryote-like)

The Eukaryotic-like glycyl-tRNA synthetase (GlyRS-E) is an enzyme that plays a crucial role in protein synthesis by catalyzing the attachment of the amino acid glycine to its cognate tRNA: $\text{Gly} + \text{tRNA}^\text{Gly} + \text{ATP} \xrightarrow{\text{GlyRS-E}} \text{Gly-tRNA}^\text{Gly} + \text{AMP} + \text{PP}_i $ GlyRS-E is a homodimeric enzyme found in eukaryotes and some archaea, and is closely related to the archaeal-like form [GlyRS-A](/class2/gly1). The two families have a catalytic domain characterized by the presence of two insertion modules, GlyRS insertion modules 1 and 2, which are located between motifs 2 and 3. Insertion module 1 contains a short $\beta$ strand which runs parallel with the six stranded anti-parallel fold, and likely recognises the acceptor stem (Qin et al. 2014). Insertion module 2 is absent in bacteria and often contains a lysine rich region, which may be involved in differentiating between cytoplasmic and mitochondrial tRNA$^\text{Gly}$ acceptor stems (Chen et al. 2012). GlyRS-E is further distinguished by the GlyRS-E insertion module nested within the catalytic domain. This insertion is intrinsically disordered and may be involved in tRNA recognition (Qin et al. 2014). These two GlyRS forms differ from the bacterial-like form [GlyRS-B](/class2/gly2), which operates as a heterotetramer and is phylogenetically distinct (Shiba 2005). GlyRS-A and -E belong to subclass IIa, which includes other enzymes such as [ProRS](/class2/pro1), [SerRS](/class2/ser1), and [ThrRS](/class2/thr) (Valencia-Sánchez et al. 2016, Perona et al. 2012). The [anticodon binding domains](/superfamily/class2/Anticodon_binding_domain_HGPT) of subclass IIa, with the exception of SerRS, are homologous with that of [HisRS](/class2/his), and are located at the C-terminal end (Wolf et al. 1999). The catalytic domain of GlyRS is typical of a Class II aminoacyl-tRNA synthetase. Like most members of the superfamily, ATP binding is coordinated by the arginine tweezers, located in motifs 2 and 3 (Kaiser et al. 2018). GlyRS-A appears to lack editing activity altogether (Gomez and Ibba, 2020). GlyRS-E is involved in a wide range of human diseases, including a serine-to-leucine mutation in its anticodon binding domain which impairs mitochondrial metabolism in neurons, associated with motor nerve degeneration (Cader et al. 2007, Boczonadi et al., 2018). GlyRS-E is one of the few aminoacyl-tRNA synthetases which operate in both the cytoplasm as well as the mitochondria, alongside [AlaRS](/class2/ala), [HisRS](/class2/his), and [ValRS](/class1/val/). Localisation into these compartments is achieved through alternative initiation, which governs the expression of an N-terminal mitochondrial localisation signal (Shiba et al. 1994, Chang et al. 2004). Some eukaryotes contain an additional GlyRS-E gene known as GRS2, which appears to be silent under normal conditions in *Saccharomyces cerevisiae* and is lacking the lysine rich insert (Chen et al. 2012).

References

Wolf, Yuri I., et al. "Evolution of aminoacyl-tRNA synthetases—analysis of unique domain architectures and phylogenetic trees reveals a complex history of horizontal gene transfer events." Genome research 9.8 (1999): 689-710. Chang, Kuang-Jung, and Chien-Chia Wang. "Translation initiation from a naturally occurring non-AUG codon in Saccharomyces cerevisiae." Journal of Biological Chemistry 279.14 (2004): 13778-13785. Qin, Xiangjing, et al. "Cocrystal structures of glycyl-tRNA synthetase in complex with tRNA suggest multiple conformational states in glycylation." Journal of Biological Chemistry 289.29 (2014): 20359-20369. Cader, Muhammed Z., et al. "Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy." FEBS letters 581.16 (2007): 2959-2964. Shiba, Kiyotaka, et al. "Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation." Journal of Biological Chemistry 269.47 (1994): 30049-30055. Perona, John J., and Andrew Hadd. "Structural diversity and protein engineering of the aminoacyl-tRNA synthetases." Biochemistry 51.44 (2012): 8705-8729. Gomez, Miguel Angel Rubio, and Michael Ibba. "Aminoacyl-tRNA synthetases." Rna 26.8 (2020): 910-936. Valencia-Sánchez, Marco Igor, et al. "Structural Insights into the Polyphyletic Origins of Glycyl tRNA Synthetases." Journal of Biological Chemistry 291.28 (2016): 14430-14446. Shiba, Kiyotaka. "The Aminoacyl-tRNA Synthetases" CRC Press (2005): Chapter 13: Glycyl-tRNA Synthetases. Chen, Shun-Jia, et al. "Saccharomyces cerevisiae possesses a stress-inducible glycyl-tRNA synthetase gene." PloS one 7.3 (2012): e33363. Boczonadi, Veronika, et al. "Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons." Human molecular genetics 27.12 (2018): 2187-2204.