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The DNAJB6 and DNAJB8 Protein Chaperones Prevent Intracellular Aggregation of Polyglutamine Peptides*
11 auth. J. Gillis, Sabine Schipper-Krom, K. Juenemann, A. Gruber, Silvia Coolen, Rianne van den Nieuwendijk, ...
Background: Intracellular aggregation of polyglutamine (polyQ) proteins can be prevented by the chaperones DNAJB6 and DNAJB8. Results: DNAJB6 and DNAJB8 prevent the aggregation of pure polyQ peptides. Conclusion: The polyQ tract is sufficient for DN…
Background: Intracellular aggregation of polyglutamine (polyQ) proteins can be prevented by the chaperones DNAJB6 and DNAJB8. Results: DNAJB6 and DNAJB8 prevent the aggregation of pure polyQ peptides. Conclusion: The polyQ tract is sufficient for DNAJB6 and DNAJB8 to prevent aggregation. Significance: By interacting with polyQ fragments, DNAJB6 and DNAJB8 reduce polyQ protein aggregation and may be potential therapeutic targets in polyQ disorders. Fragments of proteins containing an expanded polyglutamine (polyQ) tract are thought to initiate aggregation and toxicity in at least nine neurodegenerative diseases, including Huntington's disease. Because proteasomes appear unable to digest the polyQ tract, which can initiate intracellular protein aggregation, preventing polyQ peptide aggregation by chaperones should greatly improve polyQ clearance and prevent aggregate formation. Here we expressed polyQ peptides in cells and show that their intracellular aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ (Hsp40) chaperone family. In contrast, HSPA/Hsp70 and DNAJB1, also members of the DNAJ chaperone family, did not prevent peptide-initiated aggregation. Intriguingly, DNAJB6 and DNAJB8 also affected the soluble levels of polyQ peptides, indicating that DNAJB6 and DNAJB8 inhibit polyQ peptide aggregation directly. Together with recent data showing that purified DNAJB6 can suppress fibrillation of polyQ peptides far more efficiently than polyQ expanded protein fragments in vitro, we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of polyQ protein aggregation by directly binding the polyQ tract.
Published in
Journal of Biological Chemistry
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7
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7 | 2013 |
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