Key Points
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Molecular chaperones have key roles in protein quality control and recovery from stress conditions. They assist folding and unfolding and prevent or reverse aggregation of a wide range of substrates, but their actions decline with age, leading to late onset misfolding diseases.
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The major chaperone systems of the cell, namely heat shock protein 60 (HSP60), HSP70, HSP90 and HSP100, use the energy of ATP binding and hydrolysis to carry out their actions, which include stabilizing non-native proteins, unfolding misfolded proteins or folded proteins targeted for proteolysis as well as providing conditions that are favourable for folding.
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HSP70 and HSP90 are highly interactive, open structures with many exposed binding sites for co-chaperones that regulate their functions in various of biological pathways. By contrast, HSP60 and HSP100 are self-contained, with internalized active sites and few cooperating partners.
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Chaperones are extremely flexible and dynamic machines. In order to act on their substrates, their domains rotate up to 100° and are displaced by up to 50 Å or more.
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ATP binding and hydrolysis influence the accessibility and dynamics of binding sites for non-native proteins. For example, the lid subdomain of the substrate-binding domain in HSP70 is fully opened upon interaction with the ATPase domain, whereas HSP60 converts an open ring into an enclosed container for protein folding.
Abstract
Molecular chaperones are diverse families of multidomain proteins that have evolved to assist nascent proteins to reach their native fold, protect subunits from heat shock during the assembly of complexes, prevent protein aggregation or mediate targeted unfolding and disassembly. Their increased expression in response to stress is a key factor in the health of the cell and longevity of an organism. Unlike enzymes with their precise and finely tuned active sites, chaperones are heavy-duty molecular machines that operate on a wide range of substrates. The structural basis of their mechanism of action is being unravelled (in particular for the heat shock proteins HSP60, HSP70, HSP90 and HSP100) and typically involves massive displacements of 20–30 kDa domains over distances of 20–50 Å and rotations of up to 100°.
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Acknowledgements
The author is grateful to D. Clare, C. Vaughan, J. Trapani and D. Middendorf for helpful comments on the manuscript and thanks the Wellcome Trust for funding.
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Supplementary information
Supplementary information S1 (figure)
GroEL-ATP states. (PDF 454 kb)
Supplementary information S2 (movie)
Trajectory of ATP-induced movements in a GroEL ring.The movie is an interpolation between the structures of four experimentally determined states of GroEL, starting from apo GroEL and passing through two major intermediate states of GroEL-ATP7, in which the apical domains first tilt and then expand radially, before going through the final 100º rotation to the GroES bound conformation1-3. GroES is not shown. The movements are then shown in reverse. Helices H and I, shown in red and orange respectively, denote the substrate-binding site. The green helix in the intermediate domain contains the catalytic aspartate, and the magenta helix in the equatorial domain links the nucleotide site to the inter-ring interface. 1. Braig, K. et al.The crystal structure of the bacterial chaperonin GroEL at 2.8 Å. Nature 371, 578–586 (1994). 2. Clare, D. K. et al. ATP-triggered molecular mechanics of the chaperonin GroEL. Cell 149, 113–123 (2012). 3. Xu, Z., Horwich, A. L. & Sigler, P. B. The crystal structure of the asymmetric GroEL–GroES–(ADP)7 chaperonin complex. Nature 388, 741–750 (1997). (MOV 4868 kb)
Supplementary information S3 (movie)
Trajectory of ring closure in an archaeal group II chaperonin. An interpolation between three states of an M. maripaludis chaperonin ring1 are shown with the same colour coding as in Movie 1. This thermosome has 8 subunits per ring, and the unliganded state is very expanded. The apical domains twist and close in movements that are similar to those of GroEL, but occurring in a different sequence. The extension of the red helix forms the builtin lid that takes the place of GroES. 1. Clare, D. K. et al. Multiple states of a nucleotide-bound group 2 chaperonin. Structure 16, 528–534 (2008). (MOV 2922 kb)
Supplementary information S4 (figure)
Comparison of chaperone nucleotide binding sites. (PDF 360 kb)
Glossary
- Autophagy
-
A process in which intracellular material is enclosed in a membrane compartment and delivered to the lysosome (vacuole in yeast) for degradation and recycling of the macromolecular constituents.
- Unfolded protein response
-
(UPR). A signalling system that regulates the balance between folding capacity of the endoplasmic reticulum (ER) and protein synthesis. If misfolded proteins accumulate, this pathway triggers apoptosis.
- Heat shock proteins
-
(HSPs). The expression of these proteins is greatly enhanced by increased temperature or other stress conditions. Most chaperones are HSPs.
- Allosteric machines
-
Macromolecular complexes in which the activity is indirectly modulated by binding of an effector at a site remote from the active site. This induces shifts in the domain or subunit structure that influence the conformation of the active site.
- Amyloid
-
Protein species that form deposits consisting of fibrillar protein aggregates rich in β-sheet structure. They assemble from proteins that have unfolded or misfolded. About 20 distinct protein species are associated with particular amyloid diseases.
- Methyl transverse relaxation optimized spectroscopy
-
(methyl TROSY). A method that uses selective isotope labelling of methyl groups on protein side chains with a transverse relaxation scheme optimized for methyl groups to obtain well-resolved nuclear magnetic resonance (NMR) spectra from large protein structures far beyond the normal range obtained in NMR structure determination.
- GHKL
-
An ATP-binding superfamily that includes DNA gyrase, the molecular chaperone heat shock protein 90, the DNA-mismatch-repair enzyme MutL and His kinase, which bind ATP in a characteristic bent conformation.
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Saibil, H. Chaperone machines for protein folding, unfolding and disaggregation. Nat Rev Mol Cell Biol 14, 630–642 (2013). https://doi.org/10.1038/nrm3658
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DOI: https://doi.org/10.1038/nrm3658
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