Seryl-tRNA Synthetase

Seryl-tRNA synthetase (SerRS) is an enzyme that plays a crucial role in protein synthesis by catalyzing the attachment of the amino acid serine to its cognate tRNA, as well as the tRNA of selenocysteine. These reactions proceed through the following mechanisms: $ \text{Ser} + \text{tRNA}^\text{Ser} + \text{ATP} \xrightarrow{\text{SerRS}} \text{Ser-tRNA}^\text{Ser} + \text{AMP} + \text{PP}_i $ $ \text{Ser} + \text{tRNA}^\text{Sec} + \text{ATP} \xrightarrow{\text{SerRS}} \text{Ser-tRNA}^\text{Sec} + \text{AMP} + \text{PP}_i $ This first reaction enables the incorporation of serine into the polypeptide, while the second enables incorporation of the 21st proteinogenic amino acid selenocysteine (Lee et al. 1989). The latter is achieved by incorporating selenocysteine at the position of the UGA stop codon, rather than stopping translation. The efficiency of this process is determined by a range of regulatory factors. SerRS is part of subclass IIa alongside [ProRS](/class2/pro1), [ThrRS](/class2/thr), and the [dimeric GlyRS](/class2/gly1) (Gomez and Ibba 2020, Valencia-Sánchez et al. 2016, Perona et al. 2012). SerRS stands apart from the rest of the subclass due to its abnormal tRNA binding domain. Serine is the only amino acid whose codons vary at all three positions. In the standard genetic code for instance, serine, leucine, and arginine are the only three amino acids whose set of codons contain more than one possible nucleotide at the first codon position, but serine stands alone in its acceptance of more than one possibility at the second codon position. These six codons are: UCU, UCA, UCC, UCG, AGU, and AGC. Moreover, serine has inherited additional codons in many non-standard genetic codes, including AGA and AGG in various mitochondrial genetic codes (NCBI genetic codes 5, 9, and 14), and CUG in the alternative Yeast genetic code (code 12). SerRS also recognises the UGA stop codon for incorporating selenocysteine. This idiosyncrasy has implications for tRNA binding (Weygand-Durasevic and Cusack 2005). Unlike most tRNAs which bind to their cognate aaRS via the anticodon, tRNA$^\text{Ser}$ binds to SerRS via its long variable arm (Dock-Bregon et al. 1990), and unlike most tRNA binding domains which exist as globular domains, the tRNA binding domain of SerRS is an antiparallel coiled coil. During catalysis, the coiled coil of one SerRS subunit interacts with the minor groove of the variable arm of tRNA$^\text{Ser}$ and directs its acceptor stem into the active site of the other SerRS subunit (Biou et al. 1994). The mammalian mitochondrial tRNA^Ser molecules deviate markedly from their cytosolic counterparts. Hence, the mammalian mitochondrial SerRS N-terminal domain differs in such organisms, while still retaining its coiled coil structure (Chimnaronk et al. 2005). Many animals, notably insects, contain a paralog of SerRS (seryl-tRNA synthetase-like insect mitochondrial protein, SLIMP) which forms a heterodimer with the mitochondrial SerRS and is involved in cell regulation (Guitart et al. 2010, Picchioni et al. 2019). In contrast, the C-terminal catalytic domain of SerRS is quite typical of a class II aaRS. 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 catalytic domain is a seven stranded antiparallel fold. Editing in SerRS occurs at the pre-transfer level, despite lacking an edit domain. This process has been characterized for threonine, cysteine, and serine hydroxamate (Gruic-Sovulj et al. 2007). There is also a [second class II SerRS](/class2/ser2), evolutionarily distinct from this one, which is found in methanogenic archaea (Bilokapic et al. 2006).

References

Chimnaronk, Sarin, et al. "Dual‐mode recognition of noncanonical tRNAsSer by seryl‐tRNA synthetase in mammalian mitochondria." The EMBO journal 24.19 (2005): 3369-3379. Lee, Byeong J., et al. "Identification of a selenocysteyl-tRNASer in mammalian cells that recognizes the nonsense codon, UGA." Journal of Biological Chemistry 264.17 (1989): 9724-9727. Dock-Bregon, Anne‐Catherine, et al. "The contacts of yeast tRNASer with seryl‐tRNA synthetase studied by footprinting experiments." European journal of biochemistry 188.2 (1990): 283-290. Biou, Valerie, et al. "The 2.9 Å crystal structure of T. thermophilus seryl-tRNA synthetase complexed with tRNA Ser." Science 263.5152 (1994): 1404-1410. Weygand-Durasevic, Ivana and Cusack, Stephen. "The Aminoacyl-tRNA Synthetases" CRC Press (2005): Chapter 17: Seryl-tRNA Synthetases. Gruic-Sovulj, Ita, Jasmina Rokov-Plavec, and Ivana Weygand-Durasevic. "Hydrolysis of non-cognate aminoacyl-adenylates by a class II aminoacyl-tRNA synthetase lacking an editing domain." FEBS letters 581.26 (2007): 5110-5114. 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. Bilokapic, Silvija, et al. "Structure of the unusual seryl-tRNA synthetase reveals a distinct zinc-dependent mode of substrate recognition." The EMBO journal 25.11 (2006): 2498-2509. Gomez, Miguel Angel Rubio, and Michael Ibba. "Aminoacyl-tRNA synthetases." Rna 26.8 (2020): 910-936. Guitart, Tanit, et al. "New Aminoacyl-tRNA Synthetase-like Protein in Insecta with an Essential Mitochondrial Function." Journal of Biological Chemistry 285.49 (2010): 38157-38166. Picchioni, Daria, et al. "Mitochondrial protein synthesis and mtDNA levels coordinated through an aminoacyl-tRNA synthetase subunit." Cell reports 27.1 (2019): 40-47. Douglas, J, Bouckaert, R., Carter, C., & Wills, P. R. Enzymic recognition of amino acids drove the evolution of primordial genetic codes. Research Square (2023).