Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Summers DW

PROVIDER: S-EPMC2635041 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Summers Daniel W DW Douglas Peter M PM Ren Hong-Yu HY Cyr Douglas M DM

The Journal of biological chemistry 20081204 6

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 ...[more]

PMID: 19056735

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Project description:The aim of this work was to search for the biological function of protein isoprenylation. For this purpose, peptides were synthesized and, by using a convenient protocol, were farnesylated or geranylated at the thiol group of the C-terminal cysteine. The interaction of these peptides with photoactivated rhodopsin (Rho*, which is functionally equivalent to metarhodopsin II) was studied with the use of sheep rod outer segments. The sheep rod outer segments, although chosen because of the unavailability of bovine material in the U.K., had favourable optical properties for the direct determination of spectral changes in membrane suspensions. At 20 degrees C and pH 8.0, the t((1/2)) of the conversion of metarhodopsin II (Meta II) (lambda(max) 389 nm) into Meta III (lambda(max) 463 nm) was 3.2 min (less than 1.5 min at 37 degrees C). The t((1/2)) was unaltered in the presence of non-farnesyl peptides but increased by approx. 20% with farnesyl-N-acetylcysteine, by approx. 60% with farnesyl peptide containing residues 544-558 of rhodopsin kinase and by approx. 140% with farnesyl peptide corresponding to residues 60-71 of the gamma-subunit of visual transducin. The effect of various peptides on the activities of bovine and sheep rhodopsin kinase was also studied. In this assay the non-farnesyl peptides and common detergents were found to be inactive; however, all the farnesyl peptides inhibited the activity to various extents. Cumulatively, the results show that, whereas the farnesyl peptides as well as a number of membrane-disrupting detergents affected the conversion from Meta II into Meta III, the inhibition of the activity of rhodopsin kinase was achieved only by the farnesyl peptides. The results are interpreted as showing that Meta II possesses a binding site for the recognition of the farnesyl group that can be used either by the farnesyl moiety of rhodopsin kinase or transducin to make the initial encounter, which can then develop into multivalent interactions characterized by the structure, and the desired function, of each protein.

Dataset Information

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

Publications

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

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