title: TRiC's tricks inhibit huntingtin aggregation.
abstract: In Huntington's disease, a mutated version of the huntingtin protein leads to cell death. Mutant huntingtin is known to aggregate, a process that can be inhibited by the eukaryotic chaperonin TRiC (TCP1-ring complex) in vitro and in vivo. A structural understanding of the genesis of aggregates and their modulation by cellular chaperones could facilitate the development of therapies but has been hindered by the heterogeneity of amyloid aggregates. Using cryo-electron microscopy (cryoEM) and single particle cryo-electron tomography (SPT) we characterize the growth of fibrillar aggregates of mutant huntingtin exon 1 containing an expanded polyglutamine tract with 51 residues (mhttQ51), and resolve 3-D structures of the chaperonin TRiC interacting with mhttQ51. We find that TRiC caps mhttQ51 fibril tips via the apical domains of its subunits, and also encapsulates smaller mhtt oligomers within its chamber. These two complementary mechanisms provide a structural description for TRiC's inhibition of mhttQ51 aggregation in vitro. DOI:http://dx.doi.org/10.7554/eLife.00710.001.
authors.affiliation: Department of Molecular Physiology and Biophysics , Baylor College of Medicine , Houston , United States ; National Center for Macromolecular Imaging, and the Verna and Marrs McLean Department of Biochemistry and Molecular Biology , Baylor College of Medicine , Houston , United States.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Shahmoradian
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Galaz-Montoya
authors.forename: Michael F
authors.initials: MF
authors.lastname: Schmid
authors.forename: Yao
authors.initials: Y
authors.lastname: Cong
authors.forename: Boxue
authors.initials: B
authors.lastname: Ma
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiess
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ludtke
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
mesh_terms: D020285:Cryoelectron Microscopy; D006801:Humans; D000071058:Huntingtin Protein; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: Amyloid; Cryo electron microscopy (cryoEM); Cryo electron tomography (cryoET); Huntingtin; None; Single particle tomography (SPT); TRiC chaperonin