Identification of human proteins that modify misfolding and proteotoxicity of pathogenic Ataxin-1
Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model system...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 16, 2012
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| In: |
PLoS Genetics
Year: 2012, Volume: 8, Issue: 8 |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1002897 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1371/journal.pgen.1002897 Verlag, kostenfrei, Volltext: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002897 
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| Author Notes: | Spyros Petrakis, Tamás Raskó, Jenny Russ, Ralf P. Friedrich, Martin Stroedicke, Sean-Patrick Riechers, Katja Muehlenberg, Angeli Möller, Anita Reinhardt, Arunachalam Vinayagam, Martin H. Schaefer, Michael Boutros, Hervé Tricoire, Miguel A. Andrade-Navarro, Erich E. Wanker |
| Summary: | Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model systems. By analyzing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil (CC) domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that CC domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. We found that the ataxin-1-interacting protein MED15, computationally predicted to possess an N-terminal CC domain, enhances spontaneous ataxin-1 aggregation in cell-based assays, while no such effect was observed with the truncated protein MED15ΔCC, lacking such a domain. Studies with recombinant proteins confirmed these results and demonstrated that the N-terminal CC domain of MED15 (MED15CC) per se is sufficient to promote spontaneous ataxin-1 aggregation in vitro. Moreover, we observed that a hybrid Pum1 protein harboring the MED15CC domain promotes ataxin-1 aggregation in cell model systems. In strong contrast, wild-type Pum1 lacking a CC domain did not stimulate ataxin-1 polymerization. These results suggest that proteins with CC domains are potent enhancers of polyQ-mediated protein misfolding and aggregation in vitro and in vivo. |
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| Item Description: | Gesehen am 06.06.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1002897 |