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Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis.

Publication ,  Journal Article
Lai, LB; Lai, SM; Szymanski, ES; Kapur, M; Choi, EK; Al-Hashimi, HM; Ackerman, SL; Gopalan, V
Published in: Proc Natl Acad Sci U S A
March 8, 2022

SignificanceUnderstanding 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 tRNAArgUCU 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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 8, 2022

Volume

119

Issue

10

Start / End Page

e2119529119

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Ribonuclease P
  • RNA, Transfer
  • Protein Processing, Post-Translational
  • Point Mutation
  • Nucleic Acid Conformation
  • Neurons
  • Models, Molecular
  • Mice
  • Magnesium
 

Citation

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Lai, L. B., Lai, S. M., Szymanski, E. S., Kapur, M., Choi, E. K., Al-Hashimi, H. M., … Gopalan, V. (2022). Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis. Proc Natl Acad Sci U S A, 119(10), e2119529119. https://doi.org/10.1073/pnas.2119529119
Lai, Lien B., Stella M. Lai, Eric S. Szymanski, Mridu Kapur, Edric K. Choi, Hashim M. Al-Hashimi, Susan L. Ackerman, and Venkat Gopalan. “Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis.Proc Natl Acad Sci U S A 119, no. 10 (March 8, 2022): e2119529119. https://doi.org/10.1073/pnas.2119529119.
Lai LB, Lai SM, Szymanski ES, Kapur M, Choi EK, Al-Hashimi HM, et al. Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis. Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2119529119.
Lai, Lien B., et al. “Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis.Proc Natl Acad Sci U S A, vol. 119, no. 10, Mar. 2022, p. e2119529119. Pubmed, doi:10.1073/pnas.2119529119.
Lai LB, Lai SM, Szymanski ES, Kapur M, Choi EK, Al-Hashimi HM, Ackerman SL, Gopalan V. Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis. Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2119529119.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 8, 2022

Volume

119

Issue

10

Start / End Page

e2119529119

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Ribonuclease P
  • RNA, Transfer
  • Protein Processing, Post-Translational
  • Point Mutation
  • Nucleic Acid Conformation
  • Neurons
  • Models, Molecular
  • Mice
  • Magnesium