Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 16, Issue 4, Pages 380-389Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1570
Keywords
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Funding
- NIH [R01 AG019322]
- Huntington's Disease Society of America postdoctoral fellowship
- NSF [MCB-0444049]
- Petroleum Research Fund/American Chemical Society [43138-AC4]
- Commonwealth of Pennsylvania [4100026429]
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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 (HTTNT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTTNT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTTNT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTTNT cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTTNT 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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