DOI: 10.1073/pnas.0604548103. A network of protein interactions determines polyglutamine toxicity

A network of protein interactions determines polyglutamine toxicity

10.1073/pnas.0604548103

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Several neurodegenerative diseases are associated with the toxicity of misfolded proteins. This toxicity must arise from a combination of the amino acid sequences of the misfolded proteins and their interactions with other factors in their environment. A particularly compelling example of how profoundly these intramolecular and intermolecular factors can modulate the toxicity of a misfolded protein is provided by the polyglutamine (polyQ) diseases. All of these disorders are caused by glutamine expansions in proteins that are broadly expressed, yet the nature of the proteins that harbor the glutamine expansions and the particular pathologies they produce are very different. We find, using a yeast model, that amino acid sequences that modulate polyQ toxicity in cis can also do so in trans. Furthermore, the prion conformation of the yeast protein Rnq1 and the level of expression of a suite of other glutamine-rich proteins profoundly affect polyQ toxicity. They can convert polyQ expansion proteins from toxic to benign and vice versa. Our work presents a paradigm for how a complex, dynamic interplay between intramolecular features of polyQ proteins and intermolecular factors in the cellular environment might determine the unique pathobiologies of polyQ expansion proteins.

Bibliography

Duennwald, M. L., Jagadish, S., Giorgini, F., Muchowski, P. J., & Lindquist, S. (2006). A network of protein interactions determines polyglutamine toxicity. Proceedings of the National Academy of Sciences, 103(29), 11051â11056.

Authors 5

Martin L. Duennwald (first)
Smitha Jagadish (additional)
Flaviano Giorgini (additional)
Paul J. Muchowski (additional)
Susan Lindquist (additional)

References 36 Referenced 132

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Dates

Type	When
Created	19 years, 1 month ago (July 10, 2006, 8:34 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 2:44 p.m.)
Indexed	1 month, 4 weeks ago (July 1, 2025, 1:27 p.m.)
Issued	19 years, 1 month ago (July 18, 2006)
Published	19 years, 1 month ago (July 18, 2006)
Published Online	19 years, 1 month ago (July 18, 2006)
Published Print	19 years, 1 month ago (July 18, 2006)

Funders 0

None

BibTeX

@article{Duennwald_2006, title={A network of protein interactions determines polyglutamine toxicity}, volume={103}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0604548103}, DOI={10.1073/pnas.0604548103}, number={29}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Duennwald, Martin L. and Jagadish, Smitha and Giorgini, Flaviano and Muchowski, Paul J. and Lindquist, Susan}, year={2006}, month=jul, pages={11051–11056} }

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