Abstract
Translational readthrough gives rise to low abundance proteins with C-terminal extensions beyond the stop codon. To identify functional translational readthrough, we estimated the readthrough propensity (RTP) of all stop codon contexts of the human genome by a new regression model in silico, identified a nucleotide consensus motif for high RTP by using this model, and analyzed all readthrough extensions in silico with a new predictor for peroxisomal targeting signal type 1 (PTS1). Lactate dehydrogenase B (LDHB) showed the highest combined RTP and PTS1 probability. Experimentally we show that at least 1.6% of the total cellular LDHB is targeted to the peroxisome by a conserved hidden PTS1. The readthrough-extended lactate dehydrogenase subunit LDHBx can also co-import LDHA, the other LDH subunit, into peroxisomes. Peroxisomal LDH is conserved in mammals and likely contributes to redox equivalent regeneration in peroxisomes.
Highlights
Translation of genetic information encoded in mRNAs into proteins is carried out by ribosomes
In order to develop a computational method to assess the readthrough propensity (RTP) of all human stop codon context (SCC) that would allow the identification of genes with high basal translational readthrough (BTR), we focused on SCCs comprising 15 nucleotides including and surrounding the stop codon
The nucleotide sequences of these stop contexts show no bias with respect to RTP, because the contexts and the stop codons evolved independently, and the context nucleotides are random in relation to the stop codon
Summary
Translation of genetic information encoded in mRNAs into proteins is carried out by ribosomes. If instead of release factor 1 (eRF1), a near-cognate aminoacyl-tRNA pairs with the stop codon in the ribosomal A site, the stop signal is suppressed. Such decoding of a stop codon as a sense codon is known as translational readthrough. Translation continues to the stop codon resulting in the synthesis of C-terminally extended proteins (Baranov et al, 2002; Namy et al, 2004; Firth and Brierley, 2012). Mutant tRNAs are classic stop codon suppressors, but termination occurs with less than 100% efficiency in normal physiology
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