Chaperone-client interactions: Non-specificity engenders multifunctionality

Abstract

Here, we provide an overview of the different mechanisms whereby three different chaperones, Spy, Hsp70, and Hsp60, interact with folding proteins, and we discuss how these chaperones may guide the folding process. Available evidence suggests that even a single chaperone can use many mechanisms to aid in protein folding, most likely due to the need for most chaperones to bind clients promiscuously. Chaperone mechanism may be better understood by always considering it in the context of the client's folding pathway and biological function.

Keywords: 70-kilodalton heat shock protein (Hsp70); CCT/TRiC; GroEL; Hsp60; Spy; chaperone; kinetics; molecular chaperone; protein folding; protein-protein interaction.

Figure 1.

Binding of Im7 to Spy. A, residual electron and anomalous density (READ) crystallography ensemble of Im7 6–45 (multiple colored ball and stick) binding to Spy (blue surface) in multiple folding states, ranging from unfolded to native-like (33). B, NMR paramagnetic resolution enhancement-based docking of native state full-length Im7 (multiple colored ribbons) to Spy (blue surface) (34).

Figure 2.

Binding of clients to Hsp60. A, crystal structure of a peptide client (green ribbon) binding to the apical domains of GroEL (blue surface) (96). B, cryo-EM structure of newly folded client gp23, modeled in using the structure of gp24 (yellow ribbons), bound within the GroEL-GroES complex (97). C, NMR chemical shift-Rosetta model of client p6 (pink ribbon) binding to the apical domain of CCT/TRiC (blue surface) (39).

Figure 3.

Crystal structure of Hsp70 dimerizing in client-binding mode. Two asymmetric units of DnaK are shown binding in chaperone configuration (blue surface of substrate-binding domain shown) and client configuration (orange ribbons) (91).