Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

Abstract

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

Keywords: BAG; CHIP; GrpE; Hip; Hop; Hsp110; Hsp40; Hsp70; Hsp90; J domain protein; SMADs; co-chaperones; molecular chaperones; nucleotide exchange factor; protein quality control.

Figure 1.

Domain organization of Hsp70 homolog of E. coli (DnaK), structure of Hsp70 and the ATP hydrolysis cycle. The domain organization of Hsp70 is shown according to length of sequence (a) divided into the nucleotide binding domain (NBD), interdomain linker region (linker), substrate binding domain (SBD), and the C-terminal tail region (C-term). Although the boundaries of subdomains IA and IIA are discontinuous in sequence space, blocks shown in (a) are accurately scaled by total number of amino acids in each subdomain: IA (1–37, 112–184, 363–383), IB (38–111), IIA (185–227, 310–362), and IIB (228–309). The SBD is further divided into β-SBD (396–507) and α-SBD (508–602). (b) Structure of ADP bound conformation of DnaK (PDB:2KHO). (c) Structure of ATP bound conformation of DnaK (PDB: 4B9Q). (d) Schematic of the ATP hydrolysis cycle of HSP70 and client folding.

Figure 2.

Structures of Hsp70 co-chaperones. The domain organization of Hsp70 (a) is shown according to length of sequence with the size of subdomain blocks scaled by total number of amino acids in each subdomain, as in Figure 1(a). Colored bars beneath the Hsp70 domain indicate approximate regions of Hsp70 that interact with each co-chaperone. NEF co-chaperones include (b) Hsp110 (dark blue) in complex with Hsp70 NBD (white); (c) HspBP1 (red) in complex with Hsp70 NBD subdomain IIB (white); (d) GrpE (teal and cyan) in complex with Hsp70 NBD (white); (e) Bag2 (purple and violet) Hsp70 NBD (white); and (f) Bag1 (orange) Hsp70 NBD (white). The JDP co-chaperone is (g) Hsp40 in complex with Hsp70 NBD/β-SBD/α-SBD (white, grey, charcoal). Other co-chaperones include (h) Hip (brown) in complex with Hsp70 NBD (white); (i) CHIP (lime green and forest green) in complex with Hsp70 α-SBD/C-term (charcoal and black); and (j) HOP (light blue) in complex with Hsp70 C-term (black).