Open AccessStructural basis for impaired 5′ processing of a mutant tRNA associated with defects in neuronal homeostasis
Author(s) -
Lien B. Lai,
Stella M. Lai,
Eric S. Szymanski,
Mridu Kapur,
Edric K. Choi,
Hashim M. AlHashimi,
Susan L. Ackerman,
Venkat Gopalan
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2119529119
Subject(s) - biology , biogenesis , transfer rna , mutant , mutation , neurodegeneration , point mutation , genetics , microbiology and biotechnology , rna , gene , disease , medicine , pathology
Significance Understanding and treating neurological disorders are global priorities. Some of these diseases are engendered by mutations that cause defects in the cellular synthesis of transfer RNAs (tRNAs), which function as adapter molecules that translate messenger RNAs into proteins. During tRNA biogenesis, ribonuclease P catalyzes removal of the transcribed sequence upstream of the mature tRNA. Here, we focus on a cytoplasmic tRNAArg UCU that is expressed specifically in neurons and, when harboring a particular point mutation, contributes to neurodegeneration in mice. Our results suggest that this mutation favors stable alternative structures that are not cleaved by mouse ribonuclease P and motivate a paradigm that may help to understand the molecular basis for disease-associated mutations in other tRNAs.