The chaperonin TRiC blocks a huntingtin sequence element that promotes the conformational switch to aggregation.

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 Biol

authors

Tam S,Spiess C,Auyeung W,Joachimiak L,Chen B,Poirier MA,Frydman J

doi

10.1038/nsmb.1700

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

1279-85

issue

12

eissn

1545-9993

issn

1545-9985

pii

nsmb.1700

journal_volume

16

pub_type

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