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  Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome

Ripaud, L., Chumakova, V., Antonin, M., Hastie, A. R., Pinkert, S., Körner, R., et al. (2014). Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(51), 18219-18224. doi:10.1073/pnas.1421313111.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-AA14-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-AA15-F
Genre: Journal Article

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 Creators:
Ripaud, Leslie1, Author              
Chumakova, Victoria1, Author              
Antonin, Matthias1, Author              
Hastie, Alex R.1, Author              
Pinkert, Stefan1, Author              
Körner, Roman1, Author              
Ruff, Kiersten M.2, Author
Pappu, Rohit V.2, Author
Hornburg, Daniel3, Author              
Mann, Matthias3, Author              
Hartl, Franz-Ulrich1, Author              
Hipp, Mark S.1, Author              
Affiliations:
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2external, ou_persistent22              
3Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: SACCHAROMYCES-CEREVISIAE; HUNTINGTONS-DISEASE; TRANSCRIPTION FACTOR; POLYGLUTAMINE AGGREGATION; FLANKING SEQUENCES; YEAST GENES; GTS1 GENE; TOXICITY; EXPRESSION; CHAPERONEprotein aggregation; protein misfolding; neurodegeneration; prion; polyglutamine proteins;
 Abstract: Expansion of a poly-glutamine (polyQ) repeat in a group of functionally unrelated proteins is the cause of several inherited neurodegenerative disorders, including Huntington's disease. The polyQ length-dependent aggregation and toxicity of these disease proteins can be reproduced in Saccharomyces cerevisiae. This system allowed us to screen for genes that when overexpressed reduce the toxic effects of an N-terminal fragment of mutant huntingtin with 103 Q. Surprisingly, among the identified suppressors were three proteins with Q-rich, prion-like domains (PrDs): glycine threonine serine repeat protein (Gts1p), nuclear polyadenylated RNA-binding protein 3, and minichromosome maintenance protein 1. Overexpression of the PrD of Gts1p, containing an imperfect 28 residue glutamine-alanine repeat, was sufficient for suppression of toxicity. Association with this discontinuous polyQ domain did not prevent 103Q aggregation, but altered the physical properties of the aggregates, most likely early in the assembly pathway, as reflected in their increased SDS solubility. Molecular simulations suggested that Gts1p arrests the aggregation of polyQ molecules at the level of nonfibrillar species, acting as a cap that destabilizes intermediates on path to form large fibrils. Quantitative proteomic analysis of polyQ interactors showed that expression of Gts1p reduced the interaction between polyQ and other prion-like proteins, and enhanced the association of molecular chaperones with the aggregates. These findings demonstrate that short, Q-rich peptides are able to shield the interactive surfaces of toxic forms of polyQ proteins and direct them into nontoxic aggregates.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: ISI: 000346767200045
DOI: 10.1073/pnas.1421313111
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Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Source Genre: Journal
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Publ. Info: 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA : NATL ACAD SCIENCES
Pages: - Volume / Issue: 111 (51) Sequence Number: - Start / End Page: 18219 - 18224 Identifier: ISSN: 0027-8424