Evidence for Hsp90 Co-chaperones in Regulating Hsp90 Function and Promoting Client Protein Folding

Abstract

Molecular chaperones are a diverse group of highly conserved proteins that transiently interact with partially folded polypeptide chains during normal cellular processes such as protein translation, translocation, and disassembly of protein complexes. Prior to folding or after denaturation, hydrophobic residues that are normally sequestered within a folded protein are exposed to the aqueous environment and are prone to aggregation or misfolding. Multiple classes of molecular chaperones, such as Hsp70s and Hsp40s, recognize and transiently bind polypeptides with exposed hydrophobic stretches in order to prevent misfolding. Other types of chaperones, such as Hsp90, have more specialized functions in that they appear to interact with only a subset of cellular proteins. This chapter focuses on the role of Hsp90 and partner co-chaperones in promoting the folding and activation of a diverse group of proteins with critical roles in cellular signaling and function.

Hsp90 Co-chaperones Form Plastic Genetic Networks Adapted to Client Maturation

“…The yeast Hsp90 machinery comprises a cohort of well-characterized co-chaperones (Cox and Johnson, 2018;Li et al, 2011;Sahasrabudhe et al, 2017;Siligardi et al, 2004;Smith and Toft, 1993). However, a comprehensive understanding of their genetic and functional interaction is still missing.…”

Evidence for interaction between Hsp90 and the ER membrane complex

“…Three of the six components originally identified as the EMC in yeast (Jonikas et al 2009) were identified as Hsp90 interactors in large-scale screens: EMC2, EMC5, and EMC6 (McClellan et al 2007;Zhao et al 2005). We chose to focus our initial efforts on EMC2 for two reasons: first, EMC2 encodes the only soluble, cytoplasmic EMC protein, and second, EMC2 is predicted to encode a TPR domain, an interaction motif of both well-studied and emerging Hsp90 cochaperones (Cox and Johnson 2018;Eckl and Richter 2013). The best established Hsp90 co-chaperone, Sti1p/p60/Hop, interacts with conserved residues in the extreme C-terminus of Hsp90 via its C-terminal TPR domain (Chen et al 1996;.…”

“…At present, from the results of both targeted experimental and high-throughput approaches, there are 1789 unique S. cerevisiae Hsp90 interactors curated in the online database BioGRID (Stark et al 2006), which has served as one public resource used toward building a complete picture of Hsp90 interactions in the cell (Echeverria et al 2011). These interactors may represent not only folding clients but also co-chaperone proteins that regulate and define the mechanism and client interactions of Hsp90 (Cox and Johnson 2018;Eckl and Richter 2013). While Hsp90 co-chaperones interact with different regions of Hsp90 utilizing various types of protein motifs, one of the most common interaction domains shared by Hsp90 co-chaperones is comprised of the tetratricopeptide repeat (TPR) motif; co-chaperones that interact via their TPR domain bind to highly conserved residues at the extreme Cterminus of Hsp90 (MEEVD) (Scheufler et al 2000).…”

Phosphorylation in the Charged Linker Modulates Interactions and Secretion of Hsp90β

“…The β isoform is considered to be the constitutively expressed isoform, while the α isoform is considered to be the stress inducible one, for example upon heat shock. Regulation of Hsp90 chaperone function is mediated through protein-protein interactions and post-translational modifications (PTMs) [ 8 , 9 , 10 , 11 ]. A set of proteins assisting Hsp90, the co-chaperones, allow for the fine-tuning of Hsp90 chaperoning activity and its interactions with the substrate proteins, usually referred to as the clients [ 12 ].…”