Valyl-tRNA Synthetase

Valyl-tRNA synthetase (ValRS) is an enzyme that plays a crucial role in protein synthesis by catalyzing the attachment of the amino acid valine to its cognate tRNA: $ \text{Val} + \text{tRNA}^\text{Val} + \text{ATP} \xrightarrow{\text{ValRS}} \text{Val-tRNA}^\text{Val} + \text{AMP} + \text{PP}_i $ ValRS is closely related to the [LeuRS-A](/class1/leu2), [LeuRS-B](/class1/leu1), [IleRS](/class1/ile), and [MetRS](/class1/met) families families, which comprise subclass Ia (Perona and Hadd 2012, Gomez and Ibba, 2020). Members of subclass Ia are characterized by their hydrophobic amino acid substrates, as well as the connecting peptide 2 (CP2) and zinc finger (ZF) insertions, depicted below. CP2 is a 30-40 amino acid two-helix bundle on the surface of the catalytic domain (Starzyk et al. 1987) and appears to be essential for amino acid activation (Zhou et al. 2008). Upstream from this resides a cysteine-rich zinc finger, 20-40 amino acids in length, also essential for effective aminoacylation (Nureki et al. 1993, Sugiura et al. 2000). ValRS, IleRS, and LeuRS share a post-transfer [editing domain](/superfamily/class1/Editing_domain_1a), absent from MetRS. This editing domain typically resides within the zinc finger, providing further amino acid selectivity by expelling a wide range of mistargetted amino acids such alanine, cysteine, threonine, valine, isoleucine, methionine, homocysteine, and norvaline (Gomez and Ibba, 2020). ValRS also targets misactivated amino acids, such as threonine, through pre-transfer editing activity (Fersht et al. 1976). Its discrimination first against size (i.e. by filtering out isoleucine), and second against polarity (i.e. removal of misactivated threonine) has been described as a double-sieve mechanism (Fersht et al. 1976, Fukai et al. 2000). IleRS, ValRS, and the bacterial-like LeuRS-B are further characterized by connecting peptide 3 (CP3), which contains a second zinc-finger motif in certain organisms (Fukunaga et al. 2005). Its functional role is unclear. The anticodon loop is recognised by three C-terminal domains. The first is a [helical domain](/superfamily/class1/Anticodon_binding_domain_CRIMVL), universal across the members of subclass Ia, as well as [CysRS](/class1/cys) and [ArgRS](/class1/arg).. The second is an [$\alpha$/$\beta$ domain](/superfamily/class1/C-terminal_junction_domain) which recognises the anticodon stem (Fukai et al. 2000). Lastly, a coiled coil recognises the D-loop of the tRNA (Fukai et al. 2000), however this domain is absent in archaea. ValRS is one of the few aminoacyl-tRNA synthetases which operate in both the cytoplasm as well as the mitochondria, alongside [AlaRS](/class2/ala), [GlyRS](/class2/gly3), and [HisRS](/class2/his) (Chatton et al. 1986). Phylogenetic analyses suggest that, in eukaryotes, the cytosolic ValRS was transferred from the mitochondrial form, and is therefore of bacterial origin (Brown et a. 1995). Thus, the archaeal form of ValRS stands apart from the rest of the family.

References

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