The challenge in protein folding is the production of the native, active conformation from the primary sequence information. In vivo, in the cytosolic environment, acquisition of the native conformation is in competition with proteolytic degradation and/or intracellular precipitation. Chaperone proteins assist in finding the native fold in all cellular phases, and these key components of the cellular machinery occur ubiquitously through archaea, bacteria and eukarya. Chaperonins are complex polymeric proteins that form a closed environment, the ‘Anfinsen cage’, to allow correct protein folding triggered by adenosine triphosphate hydrolysis, avoiding intermolecular aspecific aggregation. The chaperonins prevent protein unfolding and misfolding, events responsible for several human diseases, such as cancer and amyloid diseases. The chaperonins are considered potential drug targets due to their role in protein misfolding, aggregation and denaturation and in cellular signalling.

Key Concepts:

  • Proteins must fold properly to acquire their native and functional conformation.

  • Protein misfolding is characterised by the exposure of buried hydrophobic residues.

  • Protein misfolding may be followed by protein aggregation.

  • The folding of many proteins need to be assisted by other proteins to prevent misfolding and/or aggregation.

  • The chaperonins prevent protein unfolding and misfolding, events responsible for several human diseases, such as cancer and amyloid diseases.

  • The ‘Anfinsen cage’ is a closed environment that encapsulates the nonnative protein and allows correct protein folding in the internal chaperonin compartment.

Keywords: chaperones; chaperonin; protein folding; thermosome

Figure 1.

The group I chaperonin family. (a) The crystal structure of the asymmetric chaperonin complex GroEL and GroES with ADP (protein database code 1AON.pdb; at The 14 identical 58 kDa subunits in the two asymmetric rings of GroEL are represented with different colours in space‐filling format. In the top of the upper ring are visible the subunits of the heptameric cochaperonin GroES. (b) The bottom view of the same structure as in (a) shows the internal cavity of the ‘folding cage’. (c) and (d) The crystal structure of GroEL in complex with ATP (protein database code 1KP8.pdb). (c) The 14 identical subunits in GroEL are represented with different colours in space‐filling format. (d) The equatorial, intermediate and apical domains of each subunit in the two rings are shown in blue, green and orange, respectively. The figures were produced with DS Viewer Pro version 6.0 (Accelrys software, Inc.)

Figure 2.

The group II chaperonin family. (a–d) Models of Bos taurus TRiC structure obtained by cryo‐electron microscopy in the open (a, bottom view; b, side view) and closed (c, bottom view; d, side view) conformation. (e–g) Models of the archeal thermosome from Methanococcus maripaludis in the open (e, bottom view; f, side view) and closed (g, bottom view; h, side view) conformation. The 16‐subunit complex, formed by eight similar subunits arranged in two stacked rings, is represented with different colours by solid ribbon. The models of TRiC (4A0O and 4A0W) and of thermosome structure (3LOS and 3YIF) were obtained at The figures were produced with Discovery Studio 3.0 (Accelrys software, Inc.). Copyright by public domain.

Figure 3.

The alternating cycle of ATP binding and hydrolysis to GroEL. The GroEL tetradecamer and GroES are represented in a schematic view from a cut along the longitudinal plane. The GroEL is formed by two seven‐subunit rings stacked back‐to‐back. The equatorial, intermediate and apical domains of each subunit in the two rings are shown in blue, green and orange, respectively. Two nonnative proteins binding to the opposite rings are represented in blue and red. The two protein substrates progressively reach their native conformations inside the internal cavity. The apical and intermediate domains move in a concerted action on binding of ATP. ATP hydrolysis is the timer of the folding process in the ‘cage’. The folding by GroEL involves each of the two opposite rings alternately in the sequential steps represented in the scheme. The chaperonin accepts a nonnative protein in the empty ring when the opposite ring is in the GroEL–GroES–ADP complex. The ring becomes competent for folding the nonnative protein on the binding of ATP and GroES. GroES binds alternately to the two rings; its dissociation from GroEL is controlled by ATP binding to the opposite ring and is accompanied by the release of the freshly folded protein.



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Further Reading

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Zoubeidi A, Chi K and Gleave M (2010) Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clinical Cancer Research 16: 1088–1093.

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Consalvi, Valerio, and Chiaraluce, Roberta(Nov 2012) Chaperonins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003019.pub3]