title: 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.
authors.affiliation: Department of Biology, BioX Program Stanford University, Stanford, California, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tam
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiess
authors.forename: William
authors.initials: W
authors.lastname: Auyeung
authors.forename: Lukasz
authors.initials: L
authors.lastname: Joachimiak
authors.forename: Bryan
authors.initials: B
authors.lastname: Chen
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Poirier
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors*; D056404:Chaperonin Containing TCP-1 / Q000378:metabolism*; D018833:Chaperonins / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: D000682:Amyloid; C533299:CCT3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins