The science

Aminoacyl-tRNA Synthetases and Scaffolding Proteins

Aminoacyl-tRNA Synthetases (ARSs) covalently attach amino acids to the ends of tRNAs, thereby forming the first bridge between the nucleic acid and the protein worlds.  In mammalian cells eight of the ARSs are associated with a set of scaffolding proteins (AIMP1, AIMP2 and AIMP3) to form a Multi -Synthetase Complex (MSC).  During the course of evolution, ARSs have adopted signal- or metabolite-sensing and novel molecular interaction capabilities.  Most eukaryotic ARSs have additional unique domains at their extremities or even inserted into their conserved catalytic domains. The eukaryote-specific structural features have provided unique capabilities to form diverse functional protein complexes and have opened new avenues for research and therapeutic development.  In addition, it has been demonstrated that the MSC scaffolding proteins have their own rich biology.  

As pathophysiological functions and structures of eukaryotic and human ARSs were revealed, it became clear that the non-catalytic regulatory activities of these proteins were systematically acquired to meet the demand of complex higher eukaryotic systems.  The ARSs are distinguished from other known groups of specific protein networks in a few key respects:

  • They are universal with presence in all locations of cells, including extracellular space.
  • They are constitutively expressed and present at relatively high amounts. 
  • Their location and function are primarily controlled by post-translational modification rather than by transcription. 
  • They sense cellular nutrition such as amino acid levels and energy status to coordinate protein synthesis with other regulatory processes. 
  • While all tRNA synthetases work together for protein synthesis, each one works idiosyncratically and with a distinct mechanism to maintain system homeostasis. 

Several different ARSs and MSC components regulate gene expression at the levels of transcription, splicing, and translation via non-catalytic and unique mechanisms. Eukaryotes have another set of ARSs that carry out protein synthesis in mitochondria.  Some ARSs, or their antibodies, have been detected in in blood of autoimmune patients and are likely to result from controlled secretion processes. With these characteristics, ARSs can respond rapidly to many different types of stimuli and stresses to prevent system disturbance. Their unique biology thus provides opportunities as targets for both therapeutics and diagnostics. In fact, ARSs are already targets for approved and developmental medicines.

ARS charging of a tRNA with an amino acid as a prelude to incorporation into a newly synthesized protein.

Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs) are non-enzymatic scaffolding proteins that comprise the multi synthetase complex (MSC) with nine aminoacyl-tRNA synthetases in higher eukaryotes.