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Review
. 2015 Apr 10;427(7):1575-88.
doi: 10.1016/j.jmb.2015.02.004. Epub 2015 Feb 12.

How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions

Eugenia M Clerico  1 , Joseph M Tilitsky  1 , Wenli Meng  1 , Lila M Gierasch  2
Affiliations
Review

How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions

Eugenia M Clerico et al. J Mol Biol. .

Abstract

Hsp70 molecular chaperones are implicated in a wide variety of cellular processes, including protein biogenesis, protection of the proteome from stress, recovery of proteins from aggregates, facilitation of protein translocation across membranes, and more specialized roles such as disassembly of particular protein complexes. It is a fascinating question to ask how the mechanism of these deceptively simple molecular machines is matched to their roles in these wide-ranging processes. The key is a combination of the nature of the recognition and binding of Hsp70 substrates and the impact of Hsp70 action on their substrates. In many cases, the binding, which relies on interaction with an extended, accessible short hydrophobic sequence, favors more unfolded states of client proteins. The ATP-mediated dissociation of the substrate thus releases it in a relatively less folded state for downstream folding, membrane translocation, or hand-off to another chaperone. There are cases, such as regulation of the heat shock response or disassembly of clathrin coats, however, where binding of a short hydrophobic sequence selects conformational states of clients to favor their productive participation in a subsequent step. This Perspective discusses current understanding of how Hsp70 molecular chaperones recognize and act on their substrates and the relationships between these fundamental processes and the functional roles played by these molecular machines.

Keywords: Hsp70 molecular chaperone; chaperone substrates; complex disassembly; disaggregation; protein folding.

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Figures

Figure 1
Figure 1
Structures illustrating the binding of peptide substrate models by Hsp70s. a) The substrate-binding domain of the E. coli Hsp70, DnaK, bound to the heptapeptide, NRLLLTG (PDB 1dkz). Note that the peptide (purple) is in an extended conformation, cradled by the β-subdomain (green) and fully enclosed by the α-helical lid (red). b) A view from the top of the β-subdomain (after removal of the α-helical lid) showing the hydrophobic pocket of the peptide binding site that defines the 0th subsite. Greater hydrophobicity of the SBD surface is indicated by the intensity of the green color. The second leucine of the bound NR peptide interacts with the pocket.
Figure 2
Figure 2
Hsp70s function to maintain and favor the unfolded state of their substrates for a variety of downstream outcomes, including folding to the native state (N), delivery to organelles for translocation across membranes, and hand off to downstream chaperones (or degradation machinery in quality control pathways, not shown). The Hsp70 binding may occur co-translationally on a nascent chain or post-translationally to substrates that are released from the ribosome or stress-unfolded. Upon release from the Hsp70 interaction, the substrate is in an unfolded (U) or folding-competent intermediate (I) state. In this cartoon, the polypeptide substrate is shown in yellow with Hsp70 binding sites shown in cyan; an organellar targeting sequence is shown as a dashed black line. The Hsp70 subdomains are colored blue for the NBD, green for the β-subdomain of the SBD, red for the α-helical lid, and black for the unstructured C-terminal segment. In this and subsequent figures, the Hsp70 co-chaperones (J-proteins and nucleotide exchange factors) are not shown for simplicity.
Figure 3
Figure 3
Hsp70s can actively unfold misfolded states (M) and partner with other chaperones, like ClpB to undo aggregates (A). Hsp70s must bind to accessible binding sites to initiate the unfolding or disaggregation reaction. The coloring scheme is the same as in Figure 2.
Figure 4
Figure 4
Hsp70s hand off substrates to downstream chaperones, like Hsp90s. The action of the Hsp70 on substrates influences them so that they interact productively with the partner chaperone. Here the example of the glucocorticoid receptor ligand-binding domain (GR-LBD) is illustrated. As described in the text, the conformational ensemble of the GR-LBD contains locally unfolded states with an exposed Hsp70 binding site (cyan). The binding of the Hsp70 selects these conformations, which are in turn delivered in a process facilitated by co-chaperones Hop and p23 to the Hsp90 for further maturation steps. The coloring scheme is as in Figure 2.
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