Aggregation of proteins containing polyglutamine (polyQ) expansions characterizes many neurodegenerative disorders, including Huntington’s disease. Molecular chaperones modulate Huntingtin (Htt) aggregation and toxicity by an ill-defined mechanism. Here we determine how the chaperonin TRiC suppresses Htt aggregation. Surprisingly, 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 amyloid-promoting 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 the switch of polyQ tracts to an amyloidogenic conformation is accelerated by short endogenous sequence elements provides a novel target for therapeutic strategies to inhibit aggregation.

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