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

Producción científica: Article › revisión exhaustiva

385 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	380-389
Número de páginas	10
Publicación	Nature Structural and Molecular Biology
Volumen	16
N.º	4
DOI	https://doi.org/10.1038/nsmb.1570
Estado	Published - abr 2009

Nota bibliográfica

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.).

Financiación

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\u2019s 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.).

Financiadores	Número del financiador
Huntington's Disease Society of America
American Chemical Society Petroleum Research Fund
National Institutes of Health (NIH)
BrightFocus foundation postdoctoral fellowship A2021015F
Commonwealth of Pennsylvania
American Chemical Society	43138-AC4, 4100026429
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	MCB-0444049
National Institute on Aging	R01AG019322

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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AU - Conway, James F.

AU - M Gronenborn, Angela

AU - Wetzel, Ronald

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N2 - 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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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