The type I Hsp40 Ydj1 utilizes a farnesyl moiety and zinc finger-like region to suppress prion toxicity.

Type I Hsp40s are molecular chaperones that protect neurons from degeneration by modulating the aggregation state of amyloid-forming proteins. How Type I Hsp40s recognize beta-rich, amyloid-like substrates is currently unknown. Thus, we examined the mechanism for binding between the Type I Hsp40 Ydj1 and the yeast prion [RNQ+]. Ydj1 recognized the Gln/Asn-rich prion domain from Rnq1 specifically when it assembled into the amyloid-like [RNQ+] prion state. Upon deletion of YDJ1, overexpression of the Rnq1 prion domain killed yeast. Surprisingly, binding and suppression of prion domain toxicity by Ydj1 was dependent upon farnesylation of its C-terminal CAAX box and action of a zinc finger-like region. In contrast, folding of luciferase was independent of farnesylation, yet required the zinc finger-like region of Ydj1 and a conserved hydrophobic peptide-binding pocket. Type I Hsp40s contain at least three different domains that work in concert to bind different protein conformers. The combined action of a farnesyl moiety and zinc finger-like region enable Type I Hsp40s to recognize amyloid-like substrates and prevent formation of cytotoxic protein species.