Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism

Ashwani K. Thakur; Murali Jayaraman; Rakesh Mishra; Monika Thakur; Veronique M. Chellgren; In Ja L Byeon; Dalaver H. Anjum; Ravindra Kodali; Trevor P. Creamer; James F. Conway; Angela M Gronenborn; Ronald Wetzel

doi:10.1038/nsmb.1570

Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism

Ashwani K. Thakur, Murali Jayaraman, Rakesh Mishra, Monika Thakur, Veronique M. Chellgren, In Ja L Byeon, Dalaver H. Anjum, Ravindra Kodali, Trevor P. Creamer, James F. Conway, Angela M Gronenborn, Ronald Wetzel

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365 Scopus citations

Abstract

Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTT NT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTT NT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTT NT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTT NT cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTT NT and polyQ. The results indicate unprecedented complexity in how primary sequence controls aggregation within a substantially disordered peptide and have implications for the molecular mechanism of Huntington's disease.

Original language	English
Pages (from-to)	380-389
Number of pages	10
Journal	Nature Structural and Molecular Biology
Volume	16
Issue number	4
DOIs	https://doi.org/10.1038/nsmb.1570
State	Published - Apr 2009

Bibliographical note

Funding Information:
The authors acknowledge J. Ko and P. Patterson (California Institute of Technology) for the gift of the MW1 antibody, and T. Fullam (Allegheny College) for providing a set of aggregation kinetics data. We also acknowledge the following funding sources that contributed to the work described here: NIH R01 AG019322 (R.W.); Huntington’s Disease Society of America postdoctoral fellowship (V.M.C.); NSF MCB-0444049 (T.P.C.); Petroleum Research Fund/ American Chemical Society 43138-AC4 (T.P.C.); grant #4100026429 from the Commonwealth of Pennsylvania (A.M.G.).

Funding

The authors acknowledge J. Ko and P. Patterson (California Institute of Technology) for the gift of the MW1 antibody, and T. Fullam (Allegheny College) for providing a set of aggregation kinetics data. We also acknowledge the following funding sources that contributed to the work described here: NIH R01 AG019322 (R.W.); Huntington’s Disease Society of America postdoctoral fellowship (V.M.C.); NSF MCB-0444049 (T.P.C.); Petroleum Research Fund/ American Chemical Society 43138-AC4 (T.P.C.); grant #4100026429 from the Commonwealth of Pennsylvania (A.M.G.).

Funders	Funder number
Commonwealth of Pennsylvania
Huntington’s Disease Society of America
National Science Foundation Arctic Social Science Program	MCB-0444049
National Institutes of Health (NIH)
National Institute on Aging	R01AG019322
American Chemical Society	43138-AC4, 4100026429
American Chemical Society Petroleum Research Fund

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1038/nsmb.1570

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Thakur, A. K., Jayaraman, M., Mishra, R., Thakur, M., Chellgren, V. M., L Byeon, I. J., Anjum, D. H., Kodali, R., Creamer, T. P., Conway, J. F., M Gronenborn, A., & Wetzel, R. (2009). Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism. Nature Structural and Molecular Biology, 16(4), 380-389. https://doi.org/10.1038/nsmb.1570

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abstract = "Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTT NT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTT NT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTT NT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTT NT cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTT NT and polyQ. The results indicate unprecedented complexity in how primary sequence controls aggregation within a substantially disordered peptide and have implications for the molecular mechanism of Huntington's disease.",

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Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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