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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.
Highlights
The 90 kDa and 70 kDa heat shock proteins (Hsp) Hsp90 and Hsp70, respectively, are ATP-dependent molecular chaperones essential for eukaryotic life
Hsp70 is composed of two main domains: the N-terminal nucleotide-binding domain (NBD), and the C-terminal substrate-binding domain (SBD), which associates with substrate proteins by recognizing short exposed hydrophobic stretches in the initial stages of substrate folding [1,2,3,4]
Hsp90 organizing protein (Hop) is differentially expressed in diseases like cancer and in aging, and it critically regulates activities of the Hsp70–Hsp90 chaperone system
Summary
The 90 kDa and 70 kDa heat shock proteins (Hsp) Hsp90 and Hsp70, respectively, are ATP-dependent molecular chaperones essential for eukaryotic life. It is proposed that Hop facilitates the client transfer from the Hsp70 to the Hsp90 chaperone systems and thereby promotes the protein folding process. Mutating surface residues that are essential for the direct interaction between E. coli Hsp70 and Hsp90 impair binary complex formation and prevent substrate protein folding [104].
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