The 70-kDa heat shock proteins (Hsp70s) are ubiquitous molecular chaperones that act in a large variety of cellular protein folding and remodelling processes. They function virtually at all stages of the life of proteins from synthesis to degradation and are thus crucial for maintaining protein homeostasis, with direct implications for human health. A large set of co-chaperones comprising J-domain proteins and nucleotide exchange factors regulate the ATPase cycle of Hsp70s, which is allosterically coupled to substrate binding and release. Moreover, Hsp70s cooperate with other cellular chaperone systems including Hsp90, Hsp60 chaperonins, small heat shock proteins and Hsp100 AAA+ disaggregases, together constituting a dynamic and functionally versatile network for protein folding, unfolding, regulation, targeting, aggregation and disaggregation, as well as degradation. In this Review we describe recent advances that have increased our understanding of the molecular mechanisms and working principles of the Hsp70 network. This knowledge showcases how the Hsp70 chaperone system controls diverse cellular functions, and offers new opportunities for the development of chemical compounds that modulate disease-related Hsp70 activities.
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This work was supported by Deutsche Forschungsgemeinschaft (DFG) SFB1036 grants to B.B. and M.P.M., and by the Helmholtz Future Topic ‘Aging and Metabolic Programming (AMPro)’. R.R. is supported by the Minerva Foundation with funding from the Federal Ministry of Education and Research, and the Azrieli Foundation, and a research grant from the Blythe Brenden-Mann New Scientist Fund. N.B.N. is supported by a special Recruitment Grant from the Monash University Faculty of Medicine Nursing and Health Sciences with funding from the State Government of Victoria and the Australian Government.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Ribosomal exit tunnel
A tunnel through which nascent polypeptide chains exit the large ribosomal subunit during protein translation.
Complexes of proteins mediating the translocation of polypeptides across membranes.
(Also referred to as Hsp60s). Molecular chaperones assembled into large double-ring complexes with a central cavity, creating an isolated compartment in which proteins fold and are protected from aggregation. Chaperonins include the bacterial and mitochondrial GroEL–GroES system and eukaryotic CCT/TRiC.
Hsp90 is a highly conserved, ATP-dependent molecular chaperone that has critical roles in protein maturation and folding. The wide range of Hsp90 substrates include, for example, kinases, transcription factors, steroid hormone receptors and E3 ubiquitin ligases.
A highly regulated catabolic process in which cellular proteins and organelles are sequestered in a characteristic double-membrane vesicle called an autophagosome and are then degraded following vesicular fusion with a lysosome.
- Fe–S cluster proteins
Proteins containing iron–sulfur clusters, which are ubiquitous cofactors, complexed by inorganic sulfur and by the amino acid cysteine, that function as redox elements in electron-transfer reactions. Fe–S clusters are crucial for protein activity in many cellular contexts.
- Kinetic traps
Non-native low-energy conformations in which proteins can remain trapped when undergoing folding, preventing them from reaching their native fold.
- Clathrin triskelions
Clathrin structures that consist of three heavy chains and three light chains. These triskelion-shaped trimeric complexes form a lattice-like coat that promotes engulfment of a membrane-derived vesicle during endocytosis.
- Electron paramagnetic resonance
(EPR). A spectroscopic technique that detects materials and proteins that have unpaired electrons. EPR can be used to determine distances in molecules.
- Förster resonance energy transfer
(FRET). A mechanism describing the distance-dependent energy transfer between two light-sensitive dipoles, a donor molecule and an acceptor molecule. FRET is used to investigate molecular interactions and to study changes in protein conformation and structure.
- Entropic pulling
A model describing the pulling forces generated by entropy change that are utilized by Hsp70 proteins to unfold protein aggregates, disassemble clathrin cages and translocate protein across membranes.
(Endoplasmic reticulum-associated protein degradation). A process that mediates the recognition and retrograde delivery of aberrant (for example, misfolded) proteins from the ER into the cytosol for proteasome-mediated degradation.
- PolyQ proteins
Proteins containing a pathogenic elongation of a polyglutamine stretch caused by an increased number of CAG trinucleotide repeats. PolyQ expansions in huntingtin result in aggregation associated with Huntington disease. The length of the polyQ repeat is critical for disease onset.
- Amyloid fibrils
Protein fibril aggregates that can form in vitro or in vivo and contain characteristic cross-β-sheet motifs. Their formation is associated with neurodegeneration and diseases such as Alzheimer disease, Parkinson disease, Creutzfeldt–Jakob disease and type II diabetes.
- Ubiquitin adaptor
Multidomain protein that can bind ubiquitin chains on a substrate and the proteasome or autophagosome. p62 has a C-terminal domain that binds to polyubiquitylated substrates to deliver them to the proteasome (via its PB1 domain) or autophagosome (via its LIR domain).
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Rosenzweig, R., Nillegoda, N.B., Mayer, M.P. et al. The Hsp70 chaperone network. Nat Rev Mol Cell Biol 20, 665–680 (2019). https://doi.org/10.1038/s41580-019-0133-3
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