Proteome-wide determinants of co-translational chaperone binding in bacteria

Area of Science:

• Molecular Biology
• Biochemistry
• Proteomics

Background:

• Co-translational folding is crucial for protein function.
• Current methods limit understanding of chaperone interactions with nascent proteins.
• Principles governing proteome-wide co-translational chaperone binding remain unclear.

Purpose of the Study:

• To elucidate the principles of co-translational chaperone interaction.
• To develop a predictive model for chaperone binding based on protein sequence.
• To understand the roles of Trigger Factor (TF) and DnaK in nascent protein folding.

Main Methods:

• Genome-wide selective ribosome profiling.
• Single-molecule biophysical techniques.
• Computational predictions integrating AlphaFold.

Main Results:

• Chaperone binding of TF and DnaK correlates with exposed "unsatisfied residues" in partially folded proteins.
• A predictive model based on sequence accurately identifies co-translational chaperone binding sites.
• TF and DnaK preferentially bind partially folded, not unfolded, protein conformers.
• Synergistic roles of TF (intra-domain folding) and DnaK (preventing inter-domain contacts) were observed.
• The study revealed robustness within the TF, DnaK, and GroEL chaperone network.

Conclusions:

• Co-translational chaperone binding follows a general principle related to protein folding intermediates.
• Predictive rules for chaperone binding simplify the complex landscape of protein biosynthesis.
• This work provides a foundation for understanding productive and erroneous protein folding pathways.