Structural Disorder in Expanding the Functionome of Aminoacyl-tRNA Synthetases

Abstract

Over the last decade, aminoacyl-tRNA synthetases (AARSs) have emerged as a new class of regulatory proteins with widespread functions beyond their classic role in protein synthesis. The functional expansion concurs with the incorporation of new domains and motifs to AARSs and coincides with the emergence of the multi-synthetase complex (MSC) during the course of eukaryotic evolution. Notably, the new domains in AARSs are often found to be structurally disordered or to be linked to the enzyme cores via unstructured linkers. Further bioinformatic analysis performed here classifies the 20 human cytoplasmic AARSs into 3 groups based on their propensities for structural disorder. The analysis also suggests that, while the assembly of the MSC mainly involves ordered structural domains, structurally disordered regions play an important role in activating and expanding the regulatory functions of AARSs.

Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity

“…Published studies have shown that post-translational modifications, mainly phosphorylation, are key drivers of the release of ARSs from the MSC 9,23 and subsequent interaction with downstream effector molecules, as well as for activation of non-canonical functions 3,24 . For example, IFN-γ-dependent sequential phosphorylation of EPRS at Ser886 and Ser999 induces its release from the MSC to form the GAIT complex 13,25 .…”

3-Dimensional architecture of the human multi-tRNA synthetase complex

“…Structures of the catalytic and anti-codon binding domains of the AARSs are highly conserved from bacteria to vertebrates, and have been elucidated by X-ray crystallography. However, appended domains unique to complex animals are largely absent from reported structures, most likely due to dynamic, disordered linkages to the catalytic domains (Figure 1A ), and as a consequence, the structure of the mammalian MSC has remained elusive ( 23 , 24 ). The molecular size of the MSC, ∼1.0–1.2 MDa ( 14 , 22 , 25 , 26 ), is less than the ∼2 MDa, 60S eukaryotic large ribosomal subunit, however, given that RNA comprises at least half of the ribosome mass, the protein mass of the MSC is comparable to that of the 60S ribosome.…”

Multi-Omics Database Analysis of Aminoacyl-tRNA Synthetases in Cancer

“…These additional domains enable unique localizations and/or interactions with binding partners inside (cytosol and nucleus) and outside the cell [ 4 ]. For some cytoplasmic aaRSs, stable interactions between these new domains enable the formation of a multi-synthetase complex (MSC) in organisms ranging from archaea to eukaryotes [ 5 , 6 ]. In humans, the MSC comprises nine cytoplasmic aaRSs and three aaRS-interacting multi-functional proteins ( AIMP1 , AIMP2 , and AIMP3 / EEF1E1 ).…”