Hsp110 Chaperones Control Client Fate Determination in the Hsp70–Hsp90 Chaperone System

Abstract

The Hsp110 family of protein chaperones was known to promote maturation of Hsp90 client proteins. The yeast Hsp110 ortholog Sse1 is now shown to influence the decision to fold or degrade substrates of the Hsp70–Hsp90 chaperone system when maturation is compromised.

Hierarchical Functional Specificity of Cytosolic Heat Shock Protein 70 (Hsp70) Nucleotide Exchange Factors in Yeast

“…We predicted that constitutive HSR activation resulting in increased HSP abundance should protect against high levels of protein misfolding. To test this hypothesis, we challenged cells with AZC, a proline analog that incorporates into nascent chains causing protein misfolding (41,64,65). As shown in Fig.…”

“…In this capacity the chaperone is predicted to stabilize partially folded forms and to perform the "triage" decision whether to continue the folding process or present the substrate to associated ubiquitin ligases (CHIP in mammalian cells, primarily Ubr1 in yeast) to mark for degradation. We and others have implicated NEFs in control over client fate (41,42). A variant of the yeast vacuolar protease carboxypeptidase Y (CPY) has been successfully used as a model protein to study chaperone involvement in regulated protein degradation (40).…”

“…However, it is not clear how such specificity is generated, because the soluble Bag domain from Snl1 is fully competent to replace Fes1 in this process, whereas Sse1 is not (43). We also previously demonstrated that only the Hsp110 homolog Sse2, and not the same soluble portion of Snl1 (Snl1⌬N), could efficiently rescue processing of the Hsp90 substrate Ste11 (41). The answer may be that both soluble NEFs (Sse1 and Fes1) participate in targeting misfolded proteins for ubiquitination based on as yet undetermined features of a particular substrate.…”

Human Heat Shock Protein 105/110 kDa (Hsp105/110) Regulates Biogenesis and Quality Control of Misfolded Cystic Fibrosis Transmembrane Conductance Regulator at Multiple Levels

“…The mechanism by which Hsp105 regulates CFTR maturation remains unclear. Yeast Hsp105 homologue Sse1 is an Hsp90 cochaperone (7) and plays an important role in the regulation of client protein maturation and degradation in the cytosol in an NEF-dependent manner (56). It is likely that an analogous mechanism exists on the cytoplasmic face of the ER membrane, where the Hsp70-Hsp90 chaperone system actively regulates the conformational maturation of CFTR (29,30) (Fig.…”

Hsp110 expression changes in rat primary myocardial cells exposed to heat stress in vitro

“…Hsp110 is an efficient nucleotide exchange factor for both of the yeast cytosolic Hsp70s, Ssa1p and Ssb1p (Liu and Hendrickson, 2007), indicating that Hsp110 is an important regulator of Hsp70-substrate interaction (Dragovic et al, 2006;Raviol et al, 2006). Furthermore, Hsp110 uses a unique binding mode (Andreasson et al, 2008a,b) including the coupled effects of the nucleotides and interactions on the open-closed isomerization of the nucleotide binding domains (Mandal et al, 2010). Purified Hsp25, Hsp70, and Hsp110 spontaneously form a large complex (Wang et al, 2000) and act as a co-chaperone machine to maintain cellular structures (Manjili et al, 2003).…”