Journal Article

Cotranslational Protein Folding Through Non-Native Structural Intermediates

Rodnina, Marina V, Samatova, Ekaterina, Bitran, Amir, Shakhnovich, Eugene I, Wang, Siyu

2025

Overview

Cotranslational protein folding follows a distinct pathway shaped by the vectorial emergence of the peptide and spatial constraints of the ribosome exit tunnel. Variations in translation rhythm can cause misfolding linked to disease; however, predicting cotranslational folding pathways remains challenging. Here we computationally predict and experimentally validate a vectorial hierarchy of folding resolved at the atomistic level, where early intermediates are stabilized through non-native hydrophobic interactions before rearranging into the native-like fold. Disrupting these interactions destabilizes intermediates and impairs folding. The chaperone Trigger Factor alters the cotranslational folding pathway by keeping the nascent peptide dynamic until the full domain emerges. Our results highlight an unexpected role of surface-exposed residues in protein folding on the ribosome and provide tools to improve folding prediction and protein design.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Biophysics