Key Points
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Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperone machines, with the core consisting of an HSP70, a J protein and a nucleotide exchange factor (NEF). These machines function in a myriad of biological processes, including modulating polypeptide folding, degradation and translocation across membranes, as well as protein–protein interactions.
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Functional diversity of the HSP70 chaperone machinery is provided mainly by J proteins, as many J proteins can interact with the same HSP70 to regulate different functions. Apart from the characteristic HSP70-interacting J domain, J proteins are structurally highly divergent.
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The basic function of J proteins is to bind HSP70 and regulate client capture by accelerating ATP hydrolysis of HSP70s. Through different localization (for example, interactions with membranes or ribosomes), J proteins can tether HSP70 to specific sites or position HSP70 towards specific clients.
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Some J proteins bind to clients first and deliver substrates to HSP70s, thus providing client specificity or directing the fate of client processing through either refolding or degradation.
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Certain J proteins interact with folded client proteins. In this case, the HSP70 machine is involved in the modulation of protein–protein interactions. In certain instances, the HSP70 machinery can facilitate protein unfolding, rather than the more common role of protein folding.
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The three structurally unrelated families of NEFs might further contribute to the functional diversification of the core HSP70 machinery, although little is understood about how this may occur.
Abstract
Heat shock 70 kDa proteins (HSP70s) are ubiquitous molecular chaperones that function in a myriad of biological processes, modulating polypeptide folding, degradation and translocation across membranes, and protein–protein interactions. This multitude of roles is not easily reconciled with the universality of the activity of HSP70s in ATP-dependent client protein-binding and release cycles. Much of the functional diversity of the HSP70s is driven by a diverse class of cofactors: J proteins. Often, multiple J proteins function with a single HSP70. Some target HSP70 activity to clients at precise locations in cells and others bind client proteins directly, thereby delivering specific clients to HSP70 and directly determining their fate.
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Acknowledgements
H.H.K.'s work on J proteins was funded by Senter Novem (IOP genomics grant IGE03018), the Prinses Beatrix Foundation (WAR05-0129) and the High Q foundation (Grant 0944). E.A.C.'s work was funded by the National Institutes of Health grants (GM27870 and GM31107) and the Muscular Dystrophy Association. The authors wish to thank J. Hageman for his detailed work on the human J proteins and help with the bioinformatics and M. Cheetham (UK) for valuable discussions on the functionality and nomenclature of the human J proteins.
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Supplementary information
41580_2010_BFnrm2941_MOESM2_ESM.pdf
Supplementary information S1 Figure | Diversity in domain architecture of Hsp70-proteins (panel A) and Nucleotide Exchange Factors (panel B) from yeast (Saccharomyces cerevisiae) and Homo sapiens. (PDF 441 kb)
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Supplementary information S2 Figure | Domain structure of yeast (A) and human (B) J-proteins: Extension of figure 3 with all individual J-proteins from Saccharomyces cerevisiae (A) and Homo Sapiens (B) and their most prominent domain features. (PDF 831 kb)
41580_2010_BFnrm2941_MOESM4_ESM.pdf
Supplementary information S3 Figure | Chaperone networks: Hsp70 core-machines can form partnerships with at least three other Hsp-families. (PDF 1458 kb)
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DATABASES
FURTHER INFORMATION
Glossary
- Zinc finger
-
A small, functional, independently folded domain that requires the coordination of one or more zinc ions for structural stabilization. Zinc fingers vary widely in structure and can function in DNA and RNA binding, protein–protein interactions and membrane association.
- ERAD
-
A pathway along which misfolded proteins are transported from the ER to the cytosol for proteasomal degradation.
- Translocon
-
A complex of proteins that forms a channel in a membrane and is associated with the translocation of polypeptides from one cellular compartment to another.
- PolyQ protein
-
A protein containing a tract of several Glu residues. In inheritable neurodegenerative disorders such as Huntington's disease, these Glu tracts are expanded, leading to disease-causing protein aggregation.
- Histone deacetylase
-
An enzyme that removes acetyl groups from ε-N-acetyl lysines from histones and many other proteins. Acetylation (by histone acetyltransferases) and deacetylation is a common post-translational modification to regulate protein function.
- Ubiquitin-interacting motif
-
A single α-helix motif oriented either parallel or antiparallel to the central β-strand that binds ubiquitin and can assist in protein degradation by the proteasome.
- Ubiquitylation
-
The tagging of proteins with a small protein called ubiquitin by ubiquitin ligases. Tagging with multiple ubiquitin moieties leads to the binding of the tagged protein to the proteasome that will degrade it.
- Protein-disulphide isomerase with thioredoxin domain
-
A domain that can catalyse the formation and breakage of disulphide bonds between Cys residues in proteins as they fold. The typical thioredoxin fold refers to a canonical four-stranded antiparallel β-sheet sandwiched between two α-helices.
- Clathrin-coated vesicle
-
A vesicle surrounded by a polyhedral lattice of triskelion-shaped clathrin molecules that plays an important part in the selective sorting of cargo at the cell membrane, trans-Golgi network and endosomal compartments for multiple membrane traffic pathways.
- Fe–S cluster
-
An ensemble of iron and sulphide centres found in various metalloproteins and crucial for the function of many proteins.They are best known for their role in oxidation-reduction reactions of mitochondrial electron transport, but they also have regulatory roles.
- Spliceosome
-
A dynamic complex of specialized RNA and protein subunits that removes introns from a transcribed pre-mRNA segment (splicing).
- Autophagy
-
A catabolic process involving the engulfment of (usually damaged) organelles and long-lived proteins or protein aggregates by double-membrane vesicles (autophagosomes) that fuse with lysosomes, where their contents are degraded by acidic lysosomal hydrolases.
- E3 ubiquitin ligase
-
A protein that catalyses the attachment of multiple ubiquitin moieties onto a target, an already monoubiquitylated protein. Polyubiquitylation marks proteins for degradation by the proteasome.
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Kampinga, H., Craig, E. The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11, 579–592 (2010). https://doi.org/10.1038/nrm2941
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DOI: https://doi.org/10.1038/nrm2941
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