Chaperonins

Abstract

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 http://www.pdb.org/pdb/home/home.do). 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 http://www.pdb.org/pdb/home/home.do. 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.

close

References

Barral JM, Broadley SA, Schaffar G and Hartl FU (2004) Roles of molecular chaperones in protein misfolding diseases. Seminars in Cell and Developmental Biology 15: 17–29.

Cong Y, Baker ML, Jakana J et al. (2010) 4.0‐Å resolution cryo‐EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement. Proceedings of the National Academy of Sciences of the USA 107: 4967–4972.

Cong Y, Schröder GF, Meyer AS et al. (2012) Symmetry‐free cryo‐EM structures of the chaperonin TRiC along its ATPase‐driven conformational cycle. EMBO Journal 31: 720–730.

Dekker C, Roe SM, McCormack EA et al. (2011) The crystal structure of yeast CCT reveals intrinsic asymmetry of eukaryotic cytosolic chaperonins. EMBO Journal 30: 3078–3090.

Dobson CM (2004) Principles of protein folding, misfolding and aggregation. Seminars in Cell and Developmental Biology 15: 3–16.

Donnelly A and Blagg BS (2008) Novobiocin and additional inhibitors of the Hsp90 C‐terminal nucleotide‐binding pocket. Current Medicinal Chemistry 15: 2702–2717.

Ellis RJ (2005) Chaperomics: in vivo GroEL function defined. Current Biology 15: R661–R663.

Hartl FU (1996) Molecular chaperones in cellular protein folding. Nature 381: 571–580.

Hartl FU and Hayer‐Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nature Structural and Molecular Biology 16: 574–581.

Horwich AL, Fenton WA, Chapman E and Farr GW (2007) Two families of chaperonin: physiology and mechanism. Annual Review of Cell and Developmental Biology 23: 115–145.

Jewett AI and Shea JE (2010) Reconciling theories of chaperonin accelerated folding with experimental evidence. Cellular and Molecular Life Sciences 67: 255–276.

Kalisman N, Adams CM and Levitt M (2012) Subunit order of eukaryotic TRiC/CCT chaperonin by cross‐linking, mass spectrometry, and combinatorial homology modeling. Proceedings of the National Academy of Sciences of the USA 109: 2884–2889.

Kubota S, Kubota H and Nagata K (2006) Cytosolic chaperonin protects folding intermediates of Gbeta from aggregation by recognizing hydrophobic beta‐strands. Proceedings of the National Academy of Sciences of the USA 103: 8360–8365.

Leroux MR and Hartl FU (2000) Protein folding: versatility of the cytosolic chaperonin TRiC/CCT. Current Biology 10: 260–264.

Lundin VF, Leroux MR and Stirling PC (2010) Quality control of cytoskeletal proteins and human disease. Trends in Biochemical Sciences 35: 288–297.

Muñoz IG, Yébenes H, Zhou M et al. (2011) Crystal structure of the open conformation of the mammalian chaperonin CCT in complex with tubulin. Nature Structural and Molecular Biology 18: 14–19.

Ranford JC and Henderson (2002) Chaperonins in disease: mechanisms, models, and treatments. Molecular Pathology 55: 209–213.

Radford SE (2006) GroEL: more than just a folding cage. Cell 125: 831–833.

Ranson NA, White HE and Saibil HR (1998) Chaperonins. Biochemical Journal 333: 233–242.

Saibil H (2000) Molecular chaperones: containers and surfaces for folding, stabilising or unfolding proteins. Current Opinion in Structural Biology 10: 251–258.

Saibil HR and Ranson NA (2002) The chaperonin folding machine. Trends in Biochemical Sciences 27: 627–632.

Santos‐Junior RR, Sartori A, De Franco M et al. (2005) Immunomodulation and protection induced by DNA‐hsp65 vaccination in an animal model of arthritis. Human Gene Therapy 16: 1338–1345.

Slavotinek AM and Biesecker LG (2001) Unfolding the role of chaperones and chaperonins in human disease. Trends in Genetics 17: 528–535.

Spiess C, Meyer AS, Reissmann S and Frydman J (2004) Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets. Trends in Cell Biology 14: 598–604.

Valpuesta JM, Martin‐Benito J, Gomez‐Puertas P, Carrascosa JL and Willison KR (2002) Structure and function of a protein folding machine: the eukaryotic cytosolic chaperonin CCT. FEBS Letters 529: 11–16.

Yam AY, Xia Y, Lin HT et al. (2008) Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nature Structural and Molecular Biology 15: 1255–1262.

Yébenes H, Mesa P, Muñoz IG, Montoya G and Valpuesta JM (2011) Chaperonins: two rings for folding. Trends Biochemical Sciences 36: 424–432.

Young JC, Agashe VR, Siegers K and Hartl FU (2004) Pathways of chaperone‐mediated protein folding in the cytosol. Nature Reviews Molecular Cell Biology 5: 781–791.

Further Reading

Agashe VR and Hartl FU (2000) Roles of molecular chaperones in cytoplasmic protein folding. Seminars in Cell and Developmental Biology 11: 15–25.

Booth CR, Meyer AS, Cong Y et al. (2008) Mechanism of lid closure in the eukaryotic chaperonin TRiC/CCT. Nature Structural & Molecular Biology 15: 746–753.

Clare DK, Vasishtan D, Stagg S et al. (2012) ATP‐triggered conformational changes delineate substrate‐binding and ‐folding mechanics of the GroEL chaperonin. Cell 149: 113–123. Molecular Chaperone Group http://people.cryst.bbk.ac.uk/∼ubcg16z/chaperone.html

Dunn AY, Melville MW and Frydman J (2001) Review: cellular substrates of the eukaryotic chaperonin TRiC/CCT. Journal of Structural Biology 135: 176–184.

Ellis RJ (2000) Chaperone substrates inside the cell. Trends in Biochemical Sciences 25: 210–212.

Ellis RJ (2003) Protein folding: importance of the Anfinsen cage. Current Biology 13: R881–R883.

Gottesman ME and Hendrickson WA (2000) Protein folding and unfolding by E. coli chaperones and chaperonins. Current Opinion in Microbiology 3: 197–202.

Horovitz A and Willison KR (2005) Allosteric regulation of chaperonins. Current Opinion in Structural Biology 15: 646–651.

Horwich AL and Fenton WA (2009) Chaperonin‐mediated protein folding: using a central cavity to kinetically assist polypeptide chain folding. Quarterly Reviews of Biophysics 42: 83–116.

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

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Consalvi, Valerio, and Chiaraluce, Roberta(Nov 2012) Chaperonins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003019.pub3]