Lost in translation: how "dangerous" amino acids abort the extension of protein synthesis

Life depends on the precise function
of several proteins synthesized by ribosomes in cells.
This diverse proteome, known as the proteome, is maintained
by robust translational extensions of amino acid sequences that occur in ribosomes.
In all organisms, the translation mechanism that ensures that the nascent chain of peptides (long chains of amino acids) is elongated without being isolated
.
However, the elongation is not constant
.
The interaction between positively charged nascent peptides and negatively charged ribosome RNA is often interrupted
.

Studies have found that in prokaryotic cells, the nascent peptide chain not only disrupts the extension process, but also the stability
of the ribosome itself.
This type of conversion is known as premature termination of intrinsic ribosome instability (IRD).
There is evidence that IRDs are mainly triggered
by nascent polypeptides rich in aspartate and glutamate sequences at the n-terminus.
Because the translation mechanism is conserved, researchers are beginning to wonder if similar phenomena
can be seen in the cells of eukaryotes such as plants, fungi, and animals.

Recently, a team of Japanese studies led by Professor Hideki Taguchi of Tokyo Tech succeeded in providing some answers
to this question.
In their study, recently published in Nature Communications, the team used budding yeast cells and a reconstructed cell-free translation system to study the IRD phenomenon
in eukaryotes.
"Previous studies have explored the effects of
aspartate and glutamate sequences on bacterial ribosome translation.
However, not much
research has been done on eukaryotic cells.
Therefore, we chose eukaryotes like yeast to study the premature termination of translation, and whether there are any mechanisms against IRD," explains
Professor Taguchi, one of the corresponding authors of the study.

The team found that, similar to bacteria, the enrichment of nascent peptide chains of aspartate (D) or glutamate (E) in the n-terminal region of yeast cells led to the translation of IRD in yeast cells to abort.

They also found that the accumulation of peptid-trna inhibited cell growth in yeast lacking peptidyl-trna hydrolase, an essential cellular enzyme
.
The peptidyl-trna produced by IRD is cleaved by peptidyl-trna hydrolases, which recover peptidyl-trna
outside the ribosome complex.
The accumulation of these aborted peptide TRNAS is toxic because yeasts lacking this enzyme cannot grow when the IRD-prone sequence is overexpressed," Professor Taguchi said
.

However, the bioinformatics analysis performed by the team revealed unique ways
in which yeast cells reduce the risk of IRD.
They found that the proteome had biased amino acid distributions, where the translational elongation process was unfavorable to the amino acid sequence
that ran D/E in its n-terminal region.

This study provides new insights
into the elongation dynamics of eukaryotic cells and the countervailing mechanism that reduces translation defects during protein synthesis.
"Understanding the factors that influence the overall use of amino acids in the proteome can help us improve the expression
of recombinant proteins.
This is essential for the production of useful proteins with clinical and industrial applications," concluded Professor Taguchi
.