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  • The chaperonin TRiC blocks a huntingtin sequence element that promotes the conformational switch to aggregation NATURE STRUCTURAL & MOLECULAR BIOLOGY Tam, S., Spiess, C., Auyeung, W., Joachimiak, L., Chen, B., Poirier, M. A., Frydman, J. 2009; 16 (12): 1279-U98

    Abstract

    Aggregation of proteins containing polyglutamine (polyQ) expansions characterizes many neurodegenerative disorders, including Huntington's disease. Molecular chaperones modulate the aggregation and toxicity of the huntingtin (Htt) protein by an ill-defined mechanism. Here we determine how the chaperonin TRiC suppresses Htt aggregation. Unexpectedly, TRiC does not physically block the polyQ tract itself, but rather sequesters a short Htt sequence element, N-terminal to the polyQ tract, that promotes the amyloidogenic conformation. The residues of this element essential for rapid Htt aggregation are directly bound by TRiC. Our findings illustrate how molecular chaperones, which recognize hydrophobic determinants, can prevent aggregation of polar polyQ tracts associated with neurodegenerative diseases. The observation that short endogenous sequence elements can accelerate the switch of polyQ tracts to an amyloidogenic conformation provides a novel target for therapeutic strategies.

    View details for DOI 10.1038/nsmb.1700

    View details for Web of Science ID 000272609200016

    View details for PubMedID 19915590

    View details for PubMedCentralID PMC2788664