Histidyl-tRNA Synthetase

Histidyl-tRNA synthetase (HisRS) is an enzyme that plays a crucial role in protein synthesis by catalyzing the attachment of the amino acid histidine to its cognate tRNA: $ \text{His} + \text{tRNA}^\text{His} + \text{ATP} \xrightarrow{\text{HisRS}} \text{His-tRNA}^\text{His} + \text{AMP} + \text{PP}_i $ The catalytic domain of HisRS closely resembles [PheRS](/class2/phe1) and [SepRS](/class2/sep), which herein constitute subclass IIc (Douglas et al. 2023). However, its C-terminal [anticodon binding domain](/superfamily/class2/Anticodon_binding_domain_HGPT) resembles members of subclass IIa (Wolf et al. 1999), and accordingly some studies have instead classified HisRS under IIa (O'Donoghue et al. 2003, de Pouplana et al. 2001, Perona and Hadd 2012). HisRS does not have editing activity (Gomez et al. 2020). The catalytic domain of HisRS 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). HisRS has been a favorable target for studying ancestral urzyme models, consisting of around 130 amino acids. These constructs have yielded robust aminoacylation activity (Li et al. 2011, Carter Jr and Wills, 2021). The catalytic domain is characterized by the ~100 residue HisRS insertion module which resides between motifs 2 and 3 and contains a short $\beta$ strand that runs parallel with the six stranded anti-parallel fold. The module recognises the acceptor stem and undergoes vast conformational changes upon tRNA binding (Tian et al. 2015). In eukaryotes, HisRS is one of the few aminoacyl-tRNA synthetases that operate in both the cytoplasm as well as the mitochondria, alongside [AlaRS](/class2/ala/), [GlyRS](/class2/gly3/), and [ValRS](/class1/val/). Localisation into these compartments is achieved through alternative initiation, which governs the expression of an N-terminal mitochondrial localisation signal (Natsoulis et al. 1986, Chiu et al. 1992).

References

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