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Molecular chaperones in protein folding and proteostasis

Nature volume 475, pages 324–332 (2011)Cite this article

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Abstract

Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.

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Figure 1: Competing reactions of protein folding and aggregation.
Figure 2: The HSP70 chaperone cycle.
Figure 3: Folding in the GroEL–GroES chaperonin cage.
Figure 4: ATPase cycle of the HSP90 chaperone system.
Figure 5: Organization of chaperone pathways in the cytosol.
Figure 6: Protein fates in the proteostasis network.

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Acknowledgements

We thank W. Balch, A. Dillin, J. Kelly, R. Morimoto and P.Reinhart for discussions about proteostasis, and thank the members of our laboratory for comments on the manuscript. We apologize to all those whose important work could not be cited owing to space limitations.

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  1. Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, 82152, Germany

    F. Ulrich Hartl, Andreas Bracher & Manajit Hayer-Hartl

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Correspondence to F. Ulrich Hartl.

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F.U.H. is a consultant to Proteostasis Therapeutics.

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Hartl, F., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011). https://doi.org/10.1038/nature10317

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