Functional expansion of human tRNA synthetases achieved by structural inventions

Abstract

Known as an essential component of the translational apparatus, the aminoacyl-tRNA synthetase family catalyzes the first step reaction in protein synthesis, that is, to specifically attach each amino acid to its cognate tRNA. While preserving this essential role, tRNA synthetases developed other roles during evolution. Human tRNA synthetases, in particular, have diverse functions in different pathways involving angiogenesis, inflammation and apoptosis. The functional diversity is further illustrated in the association with various diseases through genetic mutations that do not affect aminoacylation or protein synthesis. Here we review the accumulated knowledge on how human tRNA synthetases used structural inventions to achieve functional expansions.

Figure 1

Appended domain/motifs in human AARSs and MSC-associated factors. Except for human AlaRS, all AARSs have appended domains compared to their bacterial or archaeal homologues. The prokaryotic catalytic domains and tRNA recognition domains are shown as white and gray boxes. N-terminal single helices are present in three class IIb AARSs (yellow boxes). Homologous GST domains are shown in the N-terminal regions of MetRS, GluProRS, ValRS and CysRS, as well as in the C-terminal regions of MSC p18 and p38. MSC p38 also contains a leucine zipper motif (LZ) (green box) and is involved in interactions with leucine zippers of MSC p43 and ArgRS.(Min—in the figure, replace p38/AIMP2 with MSC p38, and same for p43.) The EMAPII domains (blue boxes) in MSC p43 and TyrRS are related. Homologous WHEP domains are shared by five human AARSs. Many other appended domains in AARSs are idiosyncratic to each enzyme and remain to be further characterized.

Figure 2

Structures of appended domain/motifs in human AARSs and associated factors. These appended structures provide extra interfaces for protein-protein and protein-nucleic acid interactions, and are critical for the expanded functions of human AARSs. N-terminal single helices of human AspRS and LysRS are shown to illustrate the amphiphilic nature of those helices. Two protein-protein interaction interfaces are shown as irregular blue lines on MSC p18 (PDB 2uz8). Conserved residues among WHEP domains in different AARSs are shown as sticks (PDB 1x59, 16t, 2djv for human HisRS, TrpRS and MetRS, respectively, and PDB 1r1b for the second WHEP domain (R2) in GluProRS,). The putative cytokine motifs on EMAP II structures of human TyrRS (PDB 1ntg) and MSC p43 (PDB 1fl0) are shown in yellow.