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TitleTRiC's tricks inhibit huntingtin aggregation.
Journal, issue, pagesElife, Vol. 2, Page e00710, Year 2013
Publish dateJul 9, 2013
AuthorsSarah H Shahmoradian / Jesus G Galaz-Montoya / Michael F Schmid / Yao Cong / Boxue Ma / Christoph Spiess / Judith Frydman / Steven J Ludtke / Wah Chiu /
PubMed AbstractIn 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 ...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.
External linksElife / PubMed:23853712 / PubMed Central
MethodsEM (subtomogram averaging)
Resolution42.0 - 60.0 Å
Structure data

EMDB-5530:
Single particle tomography of TRiC chaperonin with internalized substrate
Method: EM (subtomogram averaging) / Resolution: 42.0 Å

EMDB-5531:
Single particle tomography of TRiC chaperonin with internalized substrate
Method: EM (subtomogram averaging) / Resolution: 42.0 Å

EMDB-5532:
Single particle tomography of TRiC chaperonin with internalized substrate
Method: EM (subtomogram averaging) / Resolution: 50.0 Å

EMDB-5533:
Single particle tomography of TRiC chaperonin with substrate at apical tips
Method: EM (subtomogram averaging) / Resolution: 60.0 Å

Source
  • Bos taurus (cattle)

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