Article (Scientific journals)
Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1.
Petrakis, Spyros; Raskó, Tamás; Russ, Jenny et al.
2012In PLoS Genetics, 8 (8), p. 1002897
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Keywords :
Animals; Ataxin-1; Ataxins; COS Cells; Chlorocebus aethiops; Escherichia coli/genetics; Humans; Mediator Complex/chemistry/genetics; Mutation; Nerve Tissue Proteins/chemistry/genetics; Nuclear Proteins/chemistry/genetics; Peptides/chemistry/genetics; Plasmids; Polymerization; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; RNA-Binding Proteins/chemistry/genetics; Recombinant Fusion Proteins/chemistry/genetics; Structure-Activity Relationship; Transfection
Abstract :
[en] 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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Author, co-author :
Petrakis, Spyros
Raskó, Tamás
Russ, Jenny
Friedrich, Ralf P.
Stroedicke, Martin
Riechers, Sean-Patrick Hermann  ;  Max Delbrueck Center for Molecular Medicine, Neuroproteomics, Berlin, Germany
Muehlenberg, Katja
Möller, Angeli
Reinhardt, Anita
Vinayagam, Arunachalam
Schaefer, Martin H.
Boutros, Michael
Tricoire, Hervé
Andrade-Navarro, Miguel A.
Wanker, Erich E.
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Title :
Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1.
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Journal title :
PLoS Genetics
Publisher :
Public Library of Science, United States - California
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Peer reviewed :
Peer Reviewed verified by ORBi
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