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The highly conserved heat shock protein 70 (Hsp70) is a ubiquitous molecular chaperone essential for maintaining cellular protein homeostasis. The related protein Hsp110 (Sse1/Sse2 in Saccharomyces cerevisiae ) functions as a nucleotide exchange factor (NEF) to regulate the protein folding activity of Hsp70. Hsp110/Sse1 also can prevent protein aggregation in vitro via its substrate-binding domain (SBD), but the cellular roles of this "holdase" activity are poorly defined. We generated and characterized an Sse1 mutant that separates, for the first time, its nucleotide exchange and substrate-binding functions. Sse1 sbd retains nucleotide-binding and nucleotide exchange activities while exhibiting severe deficiencies in chaperone holdase activity for unfolded polypeptides. In contrast, we observed no effect of the SBD mutation in reconstituted disaggregation or refolding reactions in vitro. In vivo, Sse1 sbd successfully heterodimerized with the yeast cytosolic Hsp70s Ssa and Ssb and promoted normal growth, with the exception of sensitivity to prolonged heat but not other proteotoxic stress. Moreover, Sse1 sbd was fully competent to support Hsp90-dependent signaling through heterologously expressed glucocorticoid receptor and degradation of a permanently misfolded protein, two previously defined roles for Sse1. We conclude that despite conservation among eukaryotic homologues, chaperone holdase activity is not an obligate function in the Hsp110 family.

Substrate binding by the yeast Hsp110 nucleotide exchange factor and molecular chaperone Sse1 is not obligate for its biological activities