CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells I Paper
Aminoacyl-tRNA synthetases (aaRSs) are ubiquitously expressed enzymes catalyzing the charging of tRNAs with their cognate amino acids to provide key building blocks for protein synthesis. Currently, aaRSs represent the largest family of proteins implicated in the etiology of neurodegenerative CharcotMarie-Tooth disease (CMT). Using an assay that enables detection of aminoacylation within the human cell environment, this work is the first to investigate charged tRNA in CMT patients. The results suggesthistidyl-tRNA synthetase (HisRS)-linked CMT is not caused by a loss-of-function mechanism. Further biochemical and biophysical analyses of several CMT-linked mutant HisRS proteins go on to show that disease severity is correlated with the degree of mutation-induced structural opening, thus consistent with a conformation driven gain-of-function mechanism.