Chaperonin-Mediated Protein Folding Dynamics

Proteins attain their functional three-dimensional structures through a finely tuned process of folding, which in the cellular milieu is considerably more complex than in vitro refolding assays. Central to this process are chaperonins, specialised oligomeric complexes that provide an isolated environment for nascent or stress-denatured polypeptides. Chaperonins such as GroEL/GroES in bacteria and the eukaryotic TRiC/CCT system encapsulate substrates within a hydrophilic chamber, using ATP-driven conformational cycles to stabilise non-native intermediates and prevent off-pathway aggregation. Complementing this, ribosome-associated chaperones, notably trigger factor in bacteria, engage emerging nascent chains immediately upon exit from the ribosomal tunnel, guiding early stages of cotranslational folding and modulating access of downstream chaperone systems. Recent advances have illuminated how the interplay between ribosomal confinement, chaperonin encapsulation and co-chaperone coordination governs the energetics and kinetics of the conformational search for the native state. These studies underscore the dynamic nature of folding landscapes in vivo, reveal new intermediate states that are not sampled during denaturant-driven refolding, and provide insight into how chaperonin networks support proteome homeostasis under physiological and stress conditions. The global significance of this work extends from understanding molecular evolution and quality control to informing therapeutic strategies for protein-misfolding diseases and optimising recombinant protein production.

Research from Nature Portfolio

Recent studies have mapped cotranslational chaperone-assisted folding pathways at peptide resolution, demonstrating that nascent polypeptides traverse distinct intermediate states when bound to trigger factor. Hydrogen–deuterium exchange mass spectrometry has revealed that partially folded elements of dihydrofolate reductase emerge within the ribosome exit tunnel and persist upon trigger factor engagement, priming the chain for rapid completion of folding once the C-terminus exits. Structural mapping of nascent chain–ribosome interactions has further delineated the route of the emerging polypeptide, highlighting specific ribosomal proteins that guide folding intermediates. In parallel, quantitative NMR analyses have shown that nascent chains adopt expanded ensembles on the ribosome surface, increasing solvation and reducing the entropic barrier to folding by as much as 30 kcal mol⁻¹. These thermodynamic effects promote the formation of on-pathway intermediates and safeguard against mutation-induced unfolding, revealing a fundamental role for the ribosome in shaping folding energetics and supporting protein evolution.

Chaperonin-Mediated Protein Folding Dynamics publication trend

The graph below shows the total number of articles in chaperonin-mediated protein folding dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Chaperonin: A cylindrical, ATP-dependent protein complex that encapsulates substrates to assist folding and prevent aggregation.

Cotranslational folding: The process by which nascent polypeptide chains begin to acquire structure while still being synthesised on the ribosome.

Trigger factor: A ribosome-associated chaperone in bacteria that binds emerging polypeptides and coordinates subsequent chaperone recruitment.

GroEL/GroES: A bacterial chaperonin system comprising a double-ring GroEL complex and a heptameric GroES lid that encapsulates substrates.

Hydrogen–deuterium exchange mass spectrometry: A technique that measures the exchange of backbone amide hydrogens with deuterium to probe protein folding intermediates and dynamics.

Entropic penalty: The loss of conformational entropy that a polypeptide experiences upon folding, which must be compensated by energetic interactions.

References

1. The ribosome lowers the entropic penalty of protein folding. Nature (2024).
2. Resolving chaperone-assisted protein folding on the ribosome at the peptide level. Nature Structural & Molecular Biology (2024).
3. Mechanism of chaperone coordination during cotranslational protein folding in bacteria. Molecular Cell (2024).
4. Native Capillary Electrophoresis–Mass Spectrometry of Near 1 MDa Non‐Covalent GroEL/GroES/Substrate Protein Complexes. Advanced Science (2024).
5. ATP-Triggered Conformational Changes Delineate Substrate-Binding and -Folding Mechanics of the GroEL Chaperonin. Cell (2012).