TRiC's tricks inhibit huntingtin aggregation

Sarah H. Shahmoradian, Jesus G. Galaz-Montoya, Michael F. Schmid, Yao Cong, Boxue Ma, Christoph Spiess, Judith Frydman, Steven J. Ludtke, Wah Chiu

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Article numbere00710
JournaleLife
Volume2013
Issue number2
DOIs
StatePublished - Jul 9 2013
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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