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- W2041037769 abstract "In Huntington's disease (HD) and several related disorders, the primary genetic cause is the expansion of a CAG repeat in a disease-specific gene. In HD the resulting expanded polyglutamine (polyQ) segment occurs near the huntingtin protein's N-terminus. The disease appears to reflect a gain of toxicity, with the toxic species involving a misfolded form of the mutant protein. However, the molecular details of the misfolded state remain unknown. In vivo studies have noted the presence of amyloid-like aggregates that are formed from N-terminal fragments of the mutant huntingtin protein. The internal fibril structure has remained under debate, largely due to the difficulty to elucidate it in any detail. Enabled by magic angle spinning (MAS) solid-state (ss)NMR, we have obtained site-specific structural and motional constraints on misfolded amyloid-like fibrils for polyQ peptides of various lengths as well as N-terminal huntingtin fragments. The latter includes the first ssNMR studies of U-13C,15N-labeled huntingtin exon1. Thus, we have elucidated the location and key structural features of the amyloid core. The ssNMR data reveal the configurations of the glutamines in the amyloid cores of simple polyQ and huntingtin exon1 fibrils to be very similar (despite quite different aggregation behavior). We also obtained direct insights into the non-polyQ segments and show that these “flanking domains” not only fall outside the amyloid core, but also retain remarkable dynamics. We characterize the latter by MAS ssNMR, using quantitative residue-specific measurements of relaxation as well as dipolar order parameters. The distribution and relative dynamics of amyloid and non-amyloid domains suggest a mechanism by which the flanking domains may allow huntingtin binding proteins to influence the stability and formation of fibrils. Moreover, these structural data further our understanding of huntingtin's misfolding and aggregation pathways." @default.
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- W2041037769 date "2015-01-01" @default.
- W2041037769 modified "2023-09-28" @default.
- W2041037769 title "Huntingtin N-Terminal Fragment Fibrils have a Rigid Amyloid Core Flanked by Non-Amyloid Domains with Increased Dynamics" @default.
- W2041037769 doi "https://doi.org/10.1016/j.bpj.2014.11.2114" @default.
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