Talk abstracts
Talk on Tuesday 02:20-02:40pm submitted by Venkat Gopalan
Structural basis for impaired 5′ processing of a mutant tRNA associated with neurodegeneration
Venkat Gopalan (Chemistry & Biochemistry)
Abstract:
During tRNA biogenesis, the endonuclease RNase P catalyzes removal of the transcribed sequence upstream of the mature tRNA. A point mutation in a cytoplasmic tRNAArgUCU that is expressed specifically in neurons contributes to neurodegeneration in mice. To understand the molecular basis of this neurological disease and to test the hypothesis that this mutation impairs tRNA maturation, we performed thermal denaturation, native gel electrophoresis, NMR spectroscopy, and kinetic (RNase P cleavage) experiments on this tRNAArgUCU (1). Our studies uncovered the presence of stable [Mg2+]-dependent alternative structural folds for the mutant tRNAArgUCU that may also be sampled transiently and in low abundance by the wildtype. Importantly, these findings suggest that mutation-driven re-structuring could foster non-native folds and that such conformational toggling of tRNAs poses an intrinsic risk for disease when point mutations selectively stabilize non-native states. This new paradigm may help understand the molecular basis for disease-associated mutations in other tRNAs.
References:
1. Lai LB, Lai SM, Szymanski E, Kapur M, Choi EK, Al-Hashimi HM, Ackerman S, Gopalan V (2022) Proc. Natl. Acad. Sci. USA 119: e2119529119
Keywords: RNA processing, tRNA, neurodegneration