Nascent polypeptides stabilize ribosomes for uninterrupted translation


Date:
November 15, 2021
Source:
Tokyo Institute of Technology
Summary:
Protein production (translation) is a complex process
involving machinery called ribosomes. How do cells counter
ribosomal destabilization leading to premature termination of
translation? Scientists have uncovered a novel role of nascent
protein chains in stabilizing translating ribosomes. They suggest
that longer peptide sequences spanning the ribosomal exit tunnel
and bulky amino acid residues in the tunnel entry help stabilize
the ribosome by bridging its subunits, ensuring uninterrupted
translation.



FULL STORY ========================================================================== Proteins are the key players that regulate cellular structure and
function.

DNA, which functions as the blueprint for protein synthesis, is
first transcribed into a messenger RNA (mRNA), which is further read
and translated into a polypeptide chain (a "new-born" protein) by macromolecular machines called ribosomes. Here, the ribosome essentially functions as a tunnel through which the train of mRNA passes and within
which amino acids are assembled in a sequential manner depending on the
mRNA sequences to form a polypeptide.


========================================================================== Certain intrinsic sequences in the polypeptide can, however, trigger
premature termination of translation. As protein synthesis is an
essential cellular process, this event can pose a great risk, resulting
in protein dysfunction or synthesis of incomplete proteins. In nascent
(newly synthesized) polypeptides, this interrupting sequence, which is
rich in negatively charged amino acid residues, is known as an "intrinsic ribosome destabilization" (IRD) sequence.

With such sequences scattered across the genome, how do cells avoid such
a premature termination and ensure uninterrupted translation? A team of researchers from the Tokyo Tech, led by Professor Hideki Taguchi have now answered this key question in their recently published The EMBO Journal article. "The need for a tunnel structure is not clear, given that the
primary function of the ribosome is simply to polymerize amino acids into
a polypeptide. The tunnel architecture, which spans 30 to 40 nascent polypeptides in length, may have evolved to balance the stabilization
and obstacles of translation elongation." explains Prof. Taguchi.

The researchers began by analyzing the proteome wide profile of the
bacterial model system, Escherichia coli, and identified IRD sequences
across various proteins. By constructing sequences of varying lengths
preceding the IRD motifs, they were able to show that the peptide
sequences that span the ribosomal tunnel can counteract destabilization
by the IRD sequence in a length-dependent but sequence-independent
manner. They further noted that longer sequences were associated with
better IRD lowering efficiency.

Next, they went on to investigate how properties of amino acid residues
in the nascent polypeptide and their distribution across the proteome
influence IRD.

Using various amino acid substitutions preceding the IRD sequence, they
found that residues with bulkier side chains were able to prevent IRD
more effectively than did smaller ones. Further, they observed a bias
in the sequence of amino acids across the proteome. Interestingly,
open reading frames that code for proteins were enriched in bulkier
amino acid residues towards the N-terminal regions that are translated
first. The researchers speculate that these bulky residues occupy the
entry of the ribosomal exit site, thereby stabilizing the translating
machinery by bridging the small and large ribosomal subunits. Further,
on abrogating specific proteins in the ribosomal exit tunnel they found
an increase in IRD, suggesting that interactions between the nascent
peptide and ribosomal proteins contribute to translation continuity.

Together, these findings indicate an intrinsic regulatory mechanism
wherein the nascent peptide in collaboration with the ribosomal tunnel
helps maintain ribosomal stability and continuity in translation
elongation.

Prof. Taguchi concludes by saying, "Our findings highlight a positive
feedback system wherein the ribosomal tunnel is occupied by its
own product for uninterrupted translation. We report on the role of
nascent peptide chains within the ribosomal exit tunnel in ensuring
efficient protein synthesis." The quest for stability seems to have
deep sub-cellular roots.

========================================================================== Story Source: Materials provided by Tokyo_Institute_of_Technology. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yuhei Chadani, Nobuyuki Sugata, Tatsuya Niwa, Yosuke Ito, Shintaro
Iwasaki, Hideki Taguchi. Nascent polypeptide within the exit tunnel
stabilizes the ribosome to counteract risky translation. The EMBO
Journal, 2021; DOI: 10.15252/embj.2021108299 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211115151013.htm

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