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

Because of vectorial protein translation, residues that interact in the native protein structure but are distantly separated in the primary sequence are unavailable simultaneously. Instead, there is a temporal delay during which the N-terminal interaction partner is unsatisfied and potentially vulnerable to non-native interactions. We introduce “Native Fold Delay” (NFD), a metric that integrates protein topology with translation kinetics to quantify such delays. We found that many proteins exhibit residues with NFDs in the range of tens of seconds. These residues, predominantly in well-structured, buried regions, often coincide with aggregation-prone regions. NFD correlates with co-translational engagement by the yeast Hsp70 chaperone Ssb, suggesting that native fold-delayed regions have a propensity to misfold. Supporting this, we show that proteins with long NFDs are more frequently co-translationally ubiquitinated and prone to aggregate upon Ssb deletion.