Rapidly Translated Polypeptides Are Preferred Substrates for Cotranslational Protein Degradation

Area of Science:

• Molecular Biology
• Proteomics
• Yeast Genetics

Background:

• Nascent polypeptides undergo degradation by the proteasome during ribosome synthesis, a process known as cotranslational protein degradation (CTPD).
• The precise mechanisms and substrates of CTPD remain largely undefined.
• Understanding CTPD is crucial for comprehending cellular protein homeostasis and quality control.

Purpose of the Study:

• To identify and characterize cotranslational protein degradation (CTPD) substrates in Saccharomyces cerevisiae.
• To elucidate the factors influencing CTPD targeting and efficiency.
• To investigate the relationship between CTPD and other protein properties like translation efficiency and folding.

Main Methods:

• Quantitative proteomic analysis comparing wild-type yeast to a CTPD-defective mutant.
• Measurement of ribosome-bound nascent chain abundance to identify CTPD substrates.
• Statistical analysis to correlate CTPD susceptibility with protein characteristics.

Main Results:

• Identified 289 efficient CTPD substrates among 1,422 analyzed proteins in yeast.
• Found that proteins involved in translation, ribosome biogenesis, nuclear transport, and amino acid metabolism are preferentially degraded cotranslationally.
• Demonstrated that CTPD is favored for rapidly translated, longer polypeptides, and those with N-terminal disorder.
• Observed an inverse correlation between CTPD efficiency and cotranslational folding, independent of mature protein half-life.

Conclusions:

• Established a proteome-wide profile of CTPD substrates in yeast.
• Revealed key determinants of CTPD targeting, including translation speed, polypeptide length, and N-terminal disorder.
• Provided evidence for an inverse relationship between cotranslational protein degradation and cotranslational folding.
• Highlighted the physiological significance of CTPD in protein quality control and cellular regulation.