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.
Summers
Daniel W
DW
Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599-7090, USA.
Douglas
Peter M
PM
Ren
Hong-Yu
HY
Cyr
Douglas M
DM
D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017368:Protein Prenylation / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000502:physiology*
D000682:Amyloid; D050956:HSP40 Heat-Shock Proteins; D011328:Prions; C404807:RNQ1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C070319:YDJ1 protein, S cerevisiae