Decoding the impact of disease-causing mutations in an essential aminoacyl-tRNA synthetase

Marie Sissler

doi:10.1016/j.jbc.2021.101386

Abstract

Aminoacyl-tRNA synthetases are housekeeping enzymes that catalyze the specific attachment of amino acids onto cognate tRNAs, providing building blocks for ribosomal protein synthesis. Owing to the absolutely essential nature of these enzymes, the possibility that mutations in their sequence could be the underlying cause of diseases had not been foreseen. However, we are learning of patients bearing familial mutations in aminoacyl-tRNA synthetases at an exponential rate. In a recent issue of JBC, Jin et al. analyzed the impact of two such mutations in the very special bifunctional human glutamyl-prolyl-tRNA synthetase and convincingly decode how these mutations elicit the integrated stress response.

Highlights

That renders their study just as tricky
glutamyl-prolyl-tRNA synthetase (EPRS) possesses in addition two extra domains: a GST-like domain that facilitates anchoring onto the MSC and a noncatalytic linker region made of three helix-turn-helix domains
Two EPRSs are required in the MSC to build one functional homodimeric (α2) prolyltRNA synthetase (PRS), which subsequently leads to the presence of two units of the monomeric glutamyl-tRNA synthetase (ERS)

Summary

Introduction

That renders their study just as tricky. the two populations of aaRSs, cytosolic and mitochondrial, have been identified in a drastically increasing number of reports as being mutated in patients with severe disease phenotypes [5, 6]. EPRS was first reported in 2018 as being mutated in patients with hypomyelinating leukodystrophy, a central nervous system disease [8]. All missense variants reported at that time affected the PRS catalytic domain of EPRS (Fig. 1, in orange) in “pseudohomozygous” states.

Results

Conclusion