Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1

[img] 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. and Rasko, T. and Russ, J. and Friedrich, R.P. and Stroedicke, M. and Riechers, S.P. and Muehlenberg, K. and Moeller, A. and Reinhardt, A. and Vinayagam, A. and Schaefer, M.H. and Boutros, M. and Tricoire, H. and 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 (U.S.A.)
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

Downloads

Downloads per month over past year

Open Access
MDC Library