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.
journal_name
Nat Struct Mol Bioljournal_title
Nature structural & molecular biologyauthors
Tam S,Spiess C,Auyeung W,Joachimiak L,Chen B,Poirier MA,Frydman Jdoi
10.1038/nsmb.1700subject
Has Abstractpub_date
2009-12-01 00:00:00pages
1279-85issue
12eissn
1545-9993issn
1545-9985pii
nsmb.1700journal_volume
16pub_type
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