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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

367 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 (US)
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
Externally published	Yes

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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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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title = "Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism",

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.",

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

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{\textquoteright}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.).",

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language = "English (US)",

volume = "16",

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AU - Chellgren, Veronique M.

AU - L Byeon, In Ja

AU - Anjum, Dalaver H.

AU - Kodali, Ravindra

AU - Creamer, Trevor P.

AU - Conway, James F.

AU - M Gronenborn, Angela

AU - Wetzel, Ronald

N1 - 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.).

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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.

AB - 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

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