DOI: 10.7554/elife.00710. TRiC’s tricks inhibit huntingtin aggregation

TRiC’s tricks inhibit huntingtin aggregation

10.7554/elife.00710

Crossref journal-article

eLife Sciences Publications, Ltd

eLife (4374)

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.

Authors 9

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

References 42 Referenced 74

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Dates

Type	When
Created	12 years, 1 month ago (July 9, 2013, 1:09 p.m.)
Deposited	1 year, 10 months ago (Oct. 11, 2023, 8:40 p.m.)
Indexed	2 days, 4 hours ago (Aug. 26, 2025, 3:07 a.m.)
Issued	12 years, 1 month ago (July 9, 2013)
Published	12 years, 1 month ago (July 9, 2013)
Published Online	12 years, 1 month ago (July 9, 2013)

Funders 8

National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
1. Institutos Nacionales de la Salud
2. US National Institutes of Health
3. NIH
Awards1
1. PN2EY016525
National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
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Awards1
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NIH (via W. M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia)
Awards1
1. T32EB009379
National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
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2. US National Institutes of Health
3. NIH
Awards1
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National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
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2. US National Institutes of Health
3. NIH
Awards1
1. PN2EY016525
National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
1. Institutos Nacionales de la Salud
2. US National Institutes of Health
3. NIH
Awards1
1. P41GM103832
National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
1. Institutos Nacionales de la Salud
2. US National Institutes of Health
3. NIH
Awards1
1. T32EB009379
National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
1. Institutos Nacionales de la Salud
2. US National Institutes of Health
3. NIH
Awards1
1. R01GM080139

BibTeX

@article{Shahmoradian_2013, title={TRiC’s tricks inhibit huntingtin aggregation}, volume={2}, ISSN={2050-084X}, url={http://dx.doi.org/10.7554/elife.00710}, DOI={10.7554/elife.00710}, journal={eLife}, publisher={eLife Sciences Publications, Ltd}, author={Shahmoradian, Sarah H and Galaz-Montoya, Jesus G and Schmid, Michael F and Cong, Yao and Ma, Boxue and Spiess, Christoph and Frydman, Judith and Ludtke, Steven J and Chiu, Wah}, year={2013}, month=jul }

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  "abstract": "<jats:p>In Huntington\u2019s 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\u2019s inhibition of mhttQ51 aggregation in vitro.</jats:p>",
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