Anti-amyloid activity of human DnaJB6 protein chaperone is selective

Authors

• DC Masison
• M Reidy
• C Lin
• S Kumar
• Dr Jyotsna

Abstract

Human chaperone DnaJB6, an Hsp70 co-chaperone whose defects cause myopathies, protects cells from polyglutamine toxicity and prevents purified polyglutamine and A-beta peptides from forming amyloid. Yeast prions [URE3] and [PSI] propagate as amyloid forms of Ure2 and Sup35 proteins, respectively. [PSI] prions can propagate as weak or strong variants, which differ only in the structural conformation of their amyloid cores. Here we show DnaJB6 protected yeast cells from polyglutamine toxicity and cured yeast of both [URE3] prions and weak variants of [PSI] prions, which are phenotypically similar to [URE3] prions. Unexpectedly, DnaJB6 did not affect propagation of strong [PSI] prions. In line with its anti-prion effects, DnaJB6 prevented purified Sup35 from forming amyloids at 37 °C, which produce predominantly weak [PSI] variants when used to infect yeast, but not at 4 °C, which produces mostly strong [PSI] variants. Thus, structurally distinct amyloids composed of the same protein were differentially sensitive to the anti-amyloid activity of DnaJB6 both in vitro and in vivo. These findings have important implications for strategies using DnaJB6 as a target for therapy in amyloid disorders.

Scientific Focus Area: Molecular Biology and Biochemistry

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