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Hsp70 molecular chaperones function in protein folding in a manner dependent on regulation by co‐chaperones. Hsp40s increase the low intrinsic ATPase activity of Hsp70, and nucleotide exchange factors (NEFs) remove ADP after ATP hydrolysis, enabling a new Hsp70 interaction cycle with non‐native protein substrate. Here, we show that members of the Hsp70‐related Hsp110 family cooperate with Hsp70 in protein folding in the eukaryotic cytosol. Mammalian Hsp110 and the yeast homologues Sse1p/2p catalyze efficient nucleotide exchange on Hsp70 and its orthologue in Saccharomyces cerevisiae, Ssa1p, respectively. Moreover, Sse1p has the same effect on Ssb1p, a ribosome‐associated isoform of Hsp70 in yeast. Mutational analysis revealed that the N‐terminal ATPase domain and the ultimate C‐terminus of Sse1p are required for nucleotide exchange activity. The Hsp110 homologues significantly …