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Review
. 2005 Mar;62(6):670-84.
doi: 10.1007/s00018-004-4464-6.

Hsp70 chaperones: cellular functions and molecular mechanism

M P Mayer  1 , B Bukau
Affiliations
Review

Hsp70 chaperones: cellular functions and molecular mechanism

M P Mayer et al. Cell Mol Life Sci. 2005 Mar.

Abstract

Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.

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Figures

Figure 1
Figure 1
Structural aspects of Hsp70 chaperones and their interaction with co-chaperones and substrates. (a) ATPase domain of bovine Hsc70. Secondary structure representation of the ATPase domain of bovine Hsc70 in complex with ADP, inorganic phosphate and two potassium ions. To emphasized the flexibility and shearing motion of the ATPase domain an overlay of the x-ray structure (cyan; PDB entry code 1BUP; [90]) and a model derived by NMR using the method of residual dipolar coupling (dark blue; [46]) is shown. The two structures were aligned in the program WeblabViewer (Accelrys, San Diego) using tethers in subdomain IA only. (b) Compex of the ATPase domain of DnaK with a dimer of GrpE X-ray structure of the complex of the DnaK ATPase domain (blue) and the GrpE dimer (orange and yellow; PDB entry code 1DKG; [60]). In ball-and-stick and transparent surface representation are indicated the interacting residues. The ATPase domain is rotated by about 90° as compared to the representation shown in (a) as indicated at the bottom of panel (a). (c) Compex of the ATPase domain of Hsc70 with the Bag-domain fragment of Bag-1. X-ray structure of the complex of the human Hsc70 ATPase domain (green) and a fragment of Bag-1 (magenta; PDB entry code 1HX1; [61]). The interacting residues and the potential salt bridge (K56-E268) are indicated. The ATPase domain is rotated by about 90° as compared to the representation shown in (a) as indicated at the bottom of panel (a). (d) Model of the structure of the substrate binding domain. Ribbon representation of the structure of the substrate binding domain of E. coli DnaK (PDB entry code 1DKX; [74]) with bound peptide substrate (as stick model). Indicated are residues that contact the substrate in space-filling representation and residues that form the so-called latch of H-bonds and a salt bridge in ball-and-stick representation. (e) Interaction of E. coli DnaK with a peptide substrate. X-ray structure of the β-sheet domain of E. coli DnaK (PDB entry code 1DKX; [74]) in ribbon representation in complex with the peptide NRLLLTG in stick representation. Orientation as indicated in the inset with a-helices cut away along the dashed line and rotated by 90°. H-bonds to the backbone of the substrate are indicated as dotted lines. (f) Interaction of E. coli HscA with a peptide substrate. X-ray structure of the β-sheet domain of E. coli HscA (PDB entry code 1U00; [78] in ribbon representation in complex with the peptide ELPPVKIHC in stick representation. Orientation as indicated in the inset of panel (e) with α-helices cut away along the dashed line and rotated by 90°. H-bonds to the backbone of the substrate are indicated as dotted lines. Note the inverse orientation as compared to the peptide in (e).
Figure 2
Figure 2
Model of the chaperone cycle of DnaK. In black is shown the basic cycle as elucidated for the DnaK system in E. coli. In gray are shown modifications found in the eukaryotic cytosol and endoplasmic reticulum
Figure 3
Figure 3
DnaJ and Bag-1 protein families. (a) Domain structure of the 3 DnaJ subfamilies. The different domains are marked in the following way: J, J-domain; G/F, Gly-Phe rich region; Zn, Zn2+ binding domain, C, C-terminal domain of homology. (b) Secondary structure representation of the J domain. NMR structure of the J-domain of E. coli DnaJ (PDB entry code 1XBL; [127], marked is the conserved HPD motif as ball-and-stick model. (c) Secondary structure representation of the Zn-binding and the C-terminal domain of S. cerevisiae Type I JDP Ydj1. X-ray structure of a fragment of yeast Ydj1 in complex with a peptide (red) (PDB entry code 1NLT; [128]. (d) Domain structure of the Bag family of proteins. Domains indicated: NLS, nuclear localization sequence; TRSEEX, Thr-Arg-Ser-Glu-Glu-Xaa repeat motif; Ub, ubiquitin-like domain; Bag, Bag homology region; WW, Trp-Trp-domain.
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