Search

Your search keyword '"Boteva, R"' showing total 2 results
Start Over Author "Boteva, R" Publisher cell press
2 results on '"Boteva, R"'

1. Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers.

Author

Behrends C, Langer CA, Boteva R, Böttcher UM, Stemp MJ, Schaffar G, Rao BV, Giese A, Kretzschmar H, Siegers K, and Hartl FU

Subjects
Chaperonins metabolism, DNA Repeat Expansion, Green Fluorescent Proteins analysis, HSP40 Heat-Shock Proteins metabolism, HSP70 Heat-Shock Proteins metabolism, Peptides metabolism, Protein Folding, Recombinant Fusion Proteins analysis, Repetitive Sequences, Amino Acid, Saccharomyces cerevisiae cytology, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism, Chaperonins physiology, Peptides chemistry
Abstract

Aberrant folding and fibrillar aggregation by polyglutamine (polyQ) expansion proteins are associated with cytotoxicity in Huntington's disease and other neurodegenerative disorders. Hsp70 chaperones have an inhibitory effect on fibril formation and can alleviate polyQ cytotoxicity. Here we show that the cytosolic chaperonin, TRiC, functions synergistically with Hsp70 in this process and is limiting in suppressing polyQ toxicity in a yeast model. In vitro reconstitution experiments revealed that TRiC, in cooperation with the Hsp70 system, promotes the assembly of polyQ-expanded fragments of huntingtin (Htt) into soluble oligomers of approximately 500 kDa. Similar oligomers were observed in yeast cells upon TRiC overexpression and were found to be benign, in contrast to conformationally distinct Htt oligomers of approximately 200 kDa, which accumulated at normal TRiC levels and correlated with inhibition of cell growth. We suggest that TRiC cooperates with the Hsp70 system as a key component in the cellular defense against amyloid-like protein misfolding.

Published
2006
Full Text
View/download PDF

2. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation.

Author

Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K, Hayer-Hartl M, and Hartl FU

Subjects
Animals, CREB-Binding Protein, Cell Line, Tumor, Cell Nucleus metabolism, Exons, HSP70 Heat-Shock Proteins genetics, HSP70 Heat-Shock Proteins metabolism, Huntingtin Protein, Macromolecular Substances, Mice, Molecular Chaperones genetics, Molecular Chaperones metabolism, Mutation genetics, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurodegenerative Diseases etiology, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins genetics, Nuclear Proteins metabolism, Peptides metabolism, Protein Conformation, Protein Folding, Saccharomyces cerevisiae, TATA-Box Binding Protein antagonists & inhibitors, TATA-Box Binding Protein genetics, TATA-Box Binding Protein metabolism, Trans-Activators antagonists & inhibitors, Trans-Activators genetics, Trans-Activators metabolism, Transcription Factors genetics, Transcription Factors metabolism, Nerve Tissue Proteins toxicity, Nuclear Proteins toxicity, Peptides genetics, Transcription Factors antagonists & inhibitors, Trinucleotide Repeat Expansion genetics
Abstract

The expression of polyglutamine-expanded mutant proteins in Huntington's disease and other neurodegenerative disorders is associated with the formation of intraneural inclusions. These aggregates could potentially cause cellular toxicity by sequestering essential proteins possessing normal polyQ repeats, including the transcription factors TBP and CBP. We show, in vitro and in cells, that monomers or small soluble oligomers of huntingtin exon1 accumulate in the nucleus and inhibit the function of TBP in a polyQ-dependent manner. FRET experiments indicate that these toxic forms are generated through a conformational rearrangement in huntingtin. Interaction of toxic huntingtin with the benign polyQ repeat of TBP structurally destabilizes the transcription factor, independent of the formation of insoluble coaggregates. Hsp70/Hsp40 chaperones interfere with the conformational change in mutant huntingtin and inhibit the deactivation of TBP. These results outline a molecular mechanism of cellular toxicity in polyQ disease and can explain the beneficial effects of molecular chaperones.

Published
2004
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results