# From denaturant to ribosome: rethinking chaperone requirements in cells

## TL;DR

This paper shows that proteins that can't refold in lab experiments often fold correctly in cells with the help of chaperones during their creation.

## Contribution

The study reveals that in vivo chaperone dependence does not align with in vitro refoldability, rethinking how chaperone needs are assessed.

## Key findings

- Proteins that fail to refold after denaturation can achieve native-like structure during co-translational synthesis.
- Chaperone dependence varies with temperature and cofactor installation in E. coli.
- Co-translational pathways are dominant for achieving native structure in cells.

## Abstract

Traditionally, protein refolding experiments use purified proteins that are globally unfolded with chaotropic agents or heat, whereupon chaperone-mediated refolding is scored by regained structure or activity. Yadav et al profile E. coli proteomes lacking DnaK/DnaJ or Trigger factor and find that chaperone dependence during primary biogenesis in vivo does not track with refoldability measured in vitro. Many proteins that refuse to refold after global denaturation achieve native-like structure during co-translational synthesis, while dependence on DnaK/DnaJ varies with temperature and cofactor installation. These results reposition co-translational pathways as dominant routes to native structure and argue that client lists derived from refolding assays cannot be used as simple predictors of chaperone requirements in cells.

Y. Bushman and A. Truman discuss new results by S. Fried and colleagues revealing that proteins incapable of refolding after denaturation in vitro do not reflect the requirement for chaperones for proper folding during biogenesis in vivo, in this issue of Molecular Systems Biology.