4.5 Article

The yeast model suggests the use of short peptides derived from mt LeuRS for the therapy of diseases due to mutations in several mt rRNAs

Journal

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1843, Issue 12, Pages 3065-3074

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2014.09.011

Keywords

Aminoacyl tRNA synthetases; C-term domain; Suppressive sequences; Mitochondrial diseases; Mitochondrial tRNA mutations

Funding

  1. Istituto Pasteur-Fondazione Cenci Bolognetti [RBINO6E9Z8]
  2. Telethon-Italy [GGP13097]

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We have previously established a yeast model of mitochondrial (mt) diseases. We showed that defective respiratory phenotypes due to point-mutations in mt tRN(ALeu(uuR)), tRNA(lle) and tRNA(val) could be relieved by overexpression of both cognate and non-cognate nuclearly encoded mt aminoacyl-tRNA synthetases (aaRS) LeuRS, IleRS and VaIRS. More recently, we showed that the isolated carboxy-terminal domain (Cterm) of yeast mt LeuRS, and even short peptides derived from the human Cterm, have the same suppressing abilities as the whole enzymes. In this work, we extend these results by investigating the activity of a number of mt aaRS from either class I or II towards a panel of mt tRNAs. The Cterm of both human and yeast mt LeuRS has the same spectrum of activity as mt aaRS belonging to class I and subclass a, which is the most extensive among the whole enzymes. Yeast Cterm is demonstrated to be endowed with mt targeting activity. Importantly, peptide fragments beta 30_31 and beta 32_33, derived from the human Cterm, have even higher efficiency as well as wider spectrum of activity, thus opening new avenues for therapeutic intervention. Bind-shifting experiments show that the beta O_31 peptide directly interacts with human mt tRNA(Leu(UUR)) and tRNA(ile), suggesting that the rescuing activity of isolated peptide fragments is mediated by a chaperone-like mechanism. Wide-range suppression appears to be idiosyncratic of LeuRS and its fragments, since it is not shared by Cterminal regions derived from human mt IleRS or VaIRS, which are expected to have very different structures and interactions with tRNAs. (C) 2014 Elsevier B.V. All rights reserved.

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