Phenylalanyl-tRNA Synthetase α Subunit (Archaeal-like)

The archaeal-like phenylalanyl-tRNA synthetase (PheRS-A) is an enzyme that plays a crucial role in protein synthesis by catalyzing the attachment of the amino acid phenylalanine to its cognate tRNA: $ \text{Phe} + \text{tRNA}^\text{Phe} + \text{ATP} \xrightarrow{\text{PheRS-A}} \text{Phe-tRNA}^\text{Phe} + \text{AMP} + \text{PP}_i $ The phenylalanyl-tRNA synthetases (PheRS) are considered to be one of the most evolutionarily complex enzymes among aminoacyl-tRNA synthetases (Klipcan et al. 2010). Unlike most Class II synthetases, which are homodimeric, PheRS-A operates as a heterotetramer composed of two $\alpha$ and two $\beta$ subunits $\alpha_2 \beta_2$. There are three known variants of PheRS: one found predominantly in eukaryotes/archaea, one found in bacteria [PheRS-B](/class2/phe1), and one localized to eukaryotic organelles [PheRS-M](/class2/phe5). This page specifically refers to the $\alpha$ subunit of the archaral-like variant (PheRS-A$\alpha$). Although both PheRS-A subunits possess a Class II catalytic domain, catalytic activity appears to be restricted to the $\alpha$ subunit. tRNA recognition also occurs in the $\alpha$ chain (in contrast to the bacterial tetramer, for which anticodon recognition occurs through the $\beta$ chain), and editing activity is restricted to $\beta$. The C-terminal catalytic core is similar to that of other PheRS families, as well as [HisRS](/class2/his) and [SepRS](/class2/sep), which together comprise subclass IIc (Douglas et al. 2023, Kavran et al. 2007, Perona et al. 2012, Valencia-Sánchez et al. 2016). The catalytic domain of PheRS-Aα is similar to other class II members, and contains six antiparallel strands. Like most members of the superfamily, ATP binding is coordinated by the arginine tweezers, located in motifs 2 and 3 (Kaiser et al. 2018). The PheRS-A$\alpha$ catalytic domain is characterised by the short PheRS-A; insertion module, which resides between motifs 2 and 3 (Douglas et al. 2023). The anticodon binding domain is proposed to be a short loop upstream of the catalytic core (Finarov et al. 2010). The N-terminal domains resemble DNA binding proteins, however their function roles are still under investigation (Ho et al. 2022).

References

Douglas, J, Bouckaert, R., Carter, C., & Wills, P. R. Enzymic recognition of amino acids drove the evolution of primordial genetic codes. Research Square (2023). Klipcan, Liron, et al. "Structural aspects of phenylalanylation and quality control in three major forms of phenylalanyl-tRNA synthetase." Journal of amino acids 2010 (2010). Ho, Manh Tin, et al. "α-Phenylalanyl tRNA synthetase competes with Notch signaling through its N-terminal domain." PLoS genetics 18.4 (2022): e1010185. Finarov, Igal, et al. "Structure of human cytosolic phenylalanyl-tRNA synthetase: evidence for kingdom-specific design of the active sites and tRNA binding patterns." Structure 18.3 (2010): 343-353. Fishman, Roman, et al. "Structure at 2.6 Å resolution of phenylalanyl-tRNA synthetase complexed with phenylalanyl-adenylate in the presence of manganese." Acta Crystallographica Section D: Biological Crystallography 57.11 (2001): 1534-1544. Kavran, Jennifer M., et al. "Structure of pyrrolysyl-tRNA synthetase, an archaeal enzyme for genetic code innovation." Proceedings of the National Academy of Sciences 104.27 (2007): 11268-11273. Cusack, Stephen, Michael Härtlein, and Reuben Leberman. "Sequence, structural and evolutionary relationships between class 2 aminoacyl-tRNA synthetases." Nucleic acids research 19.13 (1991): 3489-3498. 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. Safro, Mark. "The Aminoacyl-tRNA Synthetases" CRC Press (2005): Chapter 22: Phenylalanyl-tRNA Synthetases. Gomez, Miguel Angel Rubio, and Michael Ibba. "Aminoacyl-tRNA synthetases." Rna 26.8 (2020): 910-936. Kaiser, Florian, et al. "Backbone brackets and arginine tweezers delineate class I and class II aminoacyl tRNA synthetases." PLoS computational biology 14.4 (2018): e1006101. Perona, John J., and Andrew Hadd. "Structural diversity and protein engineering of the aminoacyl-tRNA synthetases." Biochemistry 51.44 (2012): 8705-8729.