Nascent polypeptides stabilize ribosomes for uninterrupted translation – sciencedaily
Proteins are the key players that regulate cell structure and function. DNA, which serves as a template for protein synthesis, is first transcribed into messenger RNA (mRNA), which is then read and translated into a polypeptide chain (a “newborn” protein) by macromolecular machines. called ribosomes. Here, the ribosome essentially functions as a tunnel through which the mRNA train passes and within which amino acids are assembled sequentially based on mRNA sequences to form a polypeptide.
However, certain intrinsic sequences of the polypeptide can trigger a premature interruption of translation. Since protein synthesis is an essential cellular process, this event can present a significant risk, leading to protein dysfunction or incomplete protein synthesis. In nascent (newly synthesized) polypeptides, this interrupt sequence, which is rich in negatively charged amino acid residues, is known as the “intrinsic ribosome destabilization” (IRD) sequence. With such sequences scattered throughout the genome, how do cells avoid such premature termination and ensure uninterrupted translation?
A team of Tokyo Tech researchers, led by Professor Hideki Taguchi, has now answered this key question in their recently published study The EMBO Journal article. “The need for a tunnel structure is not clear, since the main function of the ribosome is simply to polymerize amino acids into a polypeptide. The architecture of the tunnel, which spans 30 to 40 nascent polypeptides, may have evolved to balance stabilization and the obstacles of lengthening translation. ” explains Professor Taguchi.
The researchers began by analyzing the broad profile of the proteome 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 peptide sequences which cross 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 reduction efficiency.
Next, they investigated how the 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 larger side chains were able to inhibit IRD more effectively than smaller ones. In addition, they observed a bias in the amino acid sequence across the proteome. Interestingly, the open reading frames that code for proteins have been enriched for larger amino acid residues to the N-terminal regions that are translated first. The researchers speculate that these large residues occupy the entrance to the ribosomal exit site, thus stabilizing the translation machinery by connecting the small and large ribosomal subunits. In addition, by 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 the continuity of translation.
Taken together, these findings indicate an intrinsic regulatory mechanism in which the nascent peptide in conjunction with the ribosomal tunnel helps maintain ribosomal stability and continuity in lengthening translation.
Professor Taguchi concludes by saying: âOur results demonstrate a positive feedback system in which the ribosome tunnel is occupied by its own product for uninterrupted translation. We report the role of nascent peptide chains in the ribosomal exit tunnel to ensure efficient protein synthesis.
The quest for stability seems to have deep subcellular roots.
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