Co-chaperone CHIP promotes aggregation of ataxin-1.
Recent studies demonstrated that co-chaperone/E3 ligase CHIP (C-terminus of hsp70-interacting protein) mediates the ubiquitylation and suppresses the aggregation of polyglutamine (polyQ) proteins, such as huntingtin or ataxin-3. In this study, we investigated the effects of CHIP on the degradation of another polyQ protein ataxin-1. Interestingly CHIP associates not only with ... the polyQ-expanded ataxin-1 but also with the normal ataxin-1. Moreover, by enhancing ataxin-1 ubiquitylation, CHIP over-expression leads to a reduction in the solubility of ataxin-1 and thus increases the aggregate formation, especially that of polyQ-expanded ataxin-1. Domain analysis revealed that the TPR domain is required for the promotion of aggregation. By contrast, other co-chaperones or E3 ligases, such as BAG-1 or parkin, did not show similar effects on the aggregation of ataxin-1. Importantly, the effect of CHIP is impaired by the mutation of Ser776 of ataxin-1 whose phosphorylation is crucial for ataxin-1 aggregation. Our findings suggest that the role of CHIP in aggregation of polyQ proteins greatly varies depending on the context of full-length polyQ proteins.
Mesh Terms:
Amino Acid Sequence, Cell Line, Heredodegenerative Disorders, Nervous System, Humans, Inclusion Bodies, Molecular Chaperones, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Point Mutation, Protein Structure, Tertiary, Trinucleotide Repeat Expansion, Ubiquitin, Ubiquitin-Protein Ligases
Amino Acid Sequence, Cell Line, Heredodegenerative Disorders, Nervous System, Humans, Inclusion Bodies, Molecular Chaperones, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Point Mutation, Protein Structure, Tertiary, Trinucleotide Repeat Expansion, Ubiquitin, Ubiquitin-Protein Ligases
Mol. Cell. Neurosci.
Date: Jan. 01, 2007
PubMed ID: 17127076
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