Chaperone saturation mediates translation and protein folding efficiency

Area of Science:

• Molecular Biology
• Protein Synthesis
• Cellular Homeostasis

Background:

• The synchronization of nascent protein emergence from the ribosome and structural element formation is a long-standing question.
• Kinetically efficient translation can paradoxically lead to protein misfolding and aggregation, even with molecular chaperones present.
• The molecular mechanisms linking translation efficiency and protein folding efficiency are not well understood.

Purpose of the Study:

• To investigate the direct effect of synonymous mRNA changes on translation efficiency.
• To determine the impact of altered translation efficiency on protein levels and cellular responses.
• To elucidate the relationship between translation efficiency, protein folding, and cellular chaperone capacity.

Main Methods:

• Utilized ribosome profiling to measure translation efficiency.
• Employed protein quantitation to assess protein levels.
• Analyzed the cellular response of molecular chaperones, specifically the sigma 32 (σ32) transcriptional response in *Escherichia coli*.

Main Results:

• Synonymous changes in Firefly Luciferase (Luc) mRNA directly influenced its translation efficiency, causing up to a 70-fold difference in Luc protein levels.
• The cellular chaperone response, mediated by σ32, showed saturable properties, increasing by at most approximately 2-fold despite large changes in Luc protein.
• The σ32 response was most sensitive to perturbation when Luc mRNA exhibited intermediate translation efficiency.

Conclusions:

• Chaperone saturation limits the cell's ability to maintain protein folding homeostasis when faced with highly efficient translation.
• Translation efficiency and protein folding efficiency appear to have co-evolved for mutual sensitivity.
• These findings provide insight into the complex interplay between protein synthesis rates and the cellular machinery responsible for ensuring proper protein folding.