![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
![[thumbnail of 12526oa.pdf]](https://edoc.mdc-berlin.de/style/images/fileicons/application_pdf.png) |
PDF
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
2MB |
| Item Type: | Article |
|---|---|
| Title: | Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1 |
| Creators Name: | Petrakis, S., Rasko, T., Russ, J., Friedrich, R.P., Stroedicke, M., Riechers, S.P., Muehlenberg, K., Moeller, A., Reinhardt, A., Vinayagam, A., Schaefer, M.H., Boutros, M., Tricoire, H., Andrade-Navarro, M.A. and Wanker, E.E. |
| Abstract: | 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. |
| Keywords: | Cercopithecus aethiops, COS Cells, Escherichia coli, Mediator Complex, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Plasmids, Polymerization, Protein Folding, Recombinant Fusion Proteins, RNA-Binding Proteins, Secondary Protein Structure, Structure-Activity Relationship, Tertiary Protein Structure, Transfection |
| Source: | PLoS Genetics |
| ISSN: | 1553-7404 |
| Publisher: | Public Library of Science |
| Volume: | 8 |
| Number: | 8 |
| Page Range: | e1002897 |
| Date: | 16 August 2012 |
| Official Publication: | https://doi.org/10.1371/journal.pgen.1002897 |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
