The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration

Abstract

The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.

Keywords: Aggregation; Aging; Degradation; Molecular chaperone; Proteasome; Protein folding; Proteostasis; Stress response.

Fig. 1

The Hsp70-Hop-Hsp90 ternary molecular chaperone complex. a A schematic representation of the domain structure of Hop and of the mode of interaction of Hop with Hsp70 and Hsp90 in forming the Hsp70-Hop-Hsp90 ternary chaperone complex. Inset: a simplified model of the ternary chaperone complex used in subsequent figures. b Hsp70 and Hsp90 are the major interactors of both exogenously expressed and endogenous Hop. The images are of Ponceau S-stained membranes of immunoprecipitation experiments (IP) as indicated. TPR domain double mutant (K8A (TPR1), K229A (TPR2A)) Hop serves as a negative control (left panel) [28]. Normal mouse IgG serves as a control for the endogenous Hop immunoprecipitation (right panel). The position of immunoglobulin heavy chains is marked with an asterisk

Fig. 2

Schematic representation of the two alternate Hsp90 chaperone cycles. a Canonical Hsp90 chaperone cycle driven by the Hsp70-Hop-Hsp90 ternary chaperone complex. b Proposed model for the alternate Hsp90 chaperone cycle in the absence of Hop. The prokaryote-like Hsp70–Hsp90 binary chaperone complex drives the alternate Hsp90-mediated protein folding activities

Fig. 3

Schematic representation of the impact of Hop, together with Hsp70 and Hsp90, on both arms of proteostasis (protein folding and degradation)