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Functional defects of pathogenic human mitochondrial tRNAs related to structural fragility

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Overview

authors

  • Kelley, S. O.
  • Steinberg, S. V.
  • Schimmel, Paul

publication date

  • 2000

journal

  • Nature Structural Biology  Journal

abstract

  • Aminoacylation of transfer RNAs (tRNAs) is essential for protein synthesis. A growing number of human diseases correlate with point mutations in tRNA genes within the mitochondrial genome. These tRNAs have unique sequences that suggest they have fragile structures. However, the structural significance of pathology-related tRNA mutations and their effects on molecular function have not been explored. Here, opthalmoplegia related mutants of a human mitochondrial tRNA have been investigated. Each mutation replaces either an A-U or G-C pair in the predicted secondary structure with an A-C pair. Aminoacylation of each mutant tRNA was severely attenuated. Moreover, each strongly inhibited aminoacylation of the wild type substrate, suggesting that the effects of these mutations might not be bypassed in the potentially heteroplasmic environment of mitochondria. The function of mutant tRNAs was rescued by single compensatory mutations that restored Watson-Crick base pairing and reintroduced stability into regions of predicted secondary structure, even though the pairs introduced were different from those found in the wild type tRNA. Thus, functional defects caused by a subset of pathogenic mutations may result from the inherent structural fragility of human mitochondrial tRNAs.

subject areas

  • Humans
  • Kinetics
  • Mitochondria
  • Mutation
  • Nucleic Acid Conformation
  • RNA, Transfer
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Identity

International Standard Serial Number (ISSN)

  • 1072-8368

Digital Object Identifier (DOI)

  • 10.1038/79612

PubMed ID

  • 11017193
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Additional Document Info

start page

  • 862

end page

  • 865

volume

  • 7

issue

  • 10

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