Ubiquitin-interacting Motifs Inhibit Aggregation of PolyQ-expanded Huntingtin

Expansion of polyglutamine (polyQ) tracts within proteins underlies a number of neurodegenerative diseases, such as Huntington disease, Kennedy disease, and spinocerebellar ataxias. The resulting mutant proteins are unstable, forming insoluble aggregates that are associated with components of the ub...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-03, Vol.282 (13), p.10096-10103
Main Authors: Miller, Stephanie L.H., Scappini, Erica L., O'Bryan, John
Format: Article
Language:English
Subjects:
Amino Acid Motifs - physiology
Amino Acid Sequence
Cell Line
Humans
Huntingtin Protein
Molecular Sequence Data
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Nuclear Proteins - antagonists & inhibitors
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Peptides - antagonists & inhibitors
Peptides - genetics
Peptides - metabolism
Ubiquitin - antagonists & inhibitors
Ubiquitin - metabolism
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Summary:Expansion of polyglutamine (polyQ) tracts within proteins underlies a number of neurodegenerative diseases, such as Huntington disease, Kennedy disease, and spinocerebellar ataxias. The resulting mutant proteins are unstable, forming insoluble aggregates that are associated with components of the ubiquitin system, including ubiquitin, ubiquitin-like proteins, and proteins that bind to ubiquitin. Given the presence of these ubiquitin-binding proteins in the insoluble aggregates, we examined whether heterologous expression of short motifs that bind ubiquitin, termed ubiquitin-interacting motifs (UIMs), altered the aggregation of polyQ-expanded huntingtin (Htt), the protein product of the Huntington disease gene. We found that a subset of UIMs associated with mutant Htt. The ability to interact with ubiquitin was necessary, but not sufficient, for interaction with mutant Htt. Furthermore, we found that expression of single, isolated UIMs inhibited aggregation of mutant Htt. These data suggest that isolated UIMs might serve as potential inhibitors of polyQ-aggregation in vivo.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M611151200