Key Points
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When cells are exposed to stresses, proteins may misfold and aggregate. Molecular chaperones function in a myriad of cellular activities, including protein folding, remodelling and, in the case of yeast heat shock protein 104 (Hsp104) and bacterial ClpB, in the disaggregation of aggregated proteins.
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The oligomeric architecture of Hsp104 and ClpB is similar to other members of the HSP100 family of proteins.
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DnaK and Hsp70 collaborate during disaggregation with ClpB and Hsp104, respectively, through specific and direct interactions with the M-domain
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The M-domain of Hsp104 and ClpB modulates the ATP-dependent disaggregation activity. During the disaggregation reaction, Hsp70 and the bacterial homologue DnaK interact with the M-domain of Hsp104 and ClpB, respectively, unleashing the disaggregase activity.
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Determining how energy-dependent disaggregases reactivate aggregated proteins has important implications for the understanding and amelioration of aggregation-based diseases, such as Alzheimer's disease, Parkinson's disease and prion diseases.
Abstract
Protein quality control within the cell requires the interplay of many molecular chaperones and proteases. When this quality control system is disrupted, polypeptides follow pathways leading to misfolding, inactivity and aggregation. Among the repertoire of molecular chaperones are remarkable proteins that forcibly untangle protein aggregates, called disaggregases. Structural and biochemical studies have led to new insights into how these proteins collaborate with co-chaperones and utilize ATP to power protein disaggregation. Understanding how energy-dependent protein disaggregating machines function is universally important and clinically relevant, as protein aggregation is linked to medical conditions such as Alzheimer's disease, Parkinson's disease, amyloidosis and prion diseases.
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Acknowledgements
The authors thank J. Hoskins and M. Markovski for critical reading of the manuscript and helpful discussions. The research in the authors' laboratory was supported by the Intramural Research Program of the US National institutes of Health (NIH), the National Cancer Institute and the Center for Cancer Research.
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Glossary
- Heat shock proteins
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A group of proteins, including many chaperones, the expression of which increases when cells are exposed to high temperatures or other stress conditions.
- Aggregates
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Soluble or insoluble ensembles of misfolded proteins that interact through exposed hydrophobic regions.
- Amyloid
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Extremely stable, ordered protein aggregate that self-assembles into fibres with a cross-β structure and leads to many diseases in humans, including Alzheimer's disease and Huntington's disease.
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Doyle, S., Genest, O. & Wickner, S. Protein rescue from aggregates by powerful molecular chaperone machines. Nat Rev Mol Cell Biol 14, 617–629 (2013). https://doi.org/10.1038/nrm3660
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DOI: https://doi.org/10.1038/nrm3660
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