Native Fold Delay and its implications for co-translational chaperone binding and protein aggregation.

Area of Science:

• Molecular Biology
• Protein Biochemistry
• Biophysics

Background:

• Vectorial protein translation creates temporal delays for residues distant in primary sequence but proximal in native structure.
• These delays leave N-terminal interaction partners unsatisfied and vulnerable to non-native interactions.

Purpose of the Study:

• Introduce Native Fold Delay (NFD) as a metric quantifying temporal delays in protein folding.
• Investigate the relationship between NFD, protein structure, aggregation propensity, and chaperone interactions.

Main Methods:

• Developed the Native Fold Delay (NFD) metric integrating protein topology and translation kinetics.
• Correlated NFD with co-translational engagement by the yeast Hsp70 chaperone Ssb.
• Assessed co-translational ubiquitination and aggregation propensity in relation to NFD and Ssb deletion.

Main Results:

• Many proteins exhibit residues with NFDs in the tens of seconds, often in well-structured, buried regions.
• NFDs frequently coincide with aggregation-prone regions.
• Longer NFDs correlate with increased co-translational engagement by Ssb, higher ubiquitination, and aggregation upon Ssb deletion.

Conclusions:

• Native Fold Delay is a significant factor in protein folding dynamics and misfolding propensity.
• NFD highlights regions vulnerable to non-native interactions and aggregation during co-translational processes.
• Chaperone engagement, like by Ssb, may mitigate risks associated with native fold-delayed regions.