1. Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted
- Author
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Alan K. Okada, J. Mario Isas, Anoop Rawat, Anise Applebaum, Hui Xu, Franziska Meier, Kazuki Teranishi, Ellisa K Fultz, Ansgar B. Siemer, Ralf Langen, Nitin K. Pandey, and Jeannie Chen
- Subjects
Huntingtin ,Science ,General Physics and Astronomy ,Sequence (biology) ,macromolecular substances ,Fibril ,General Biochemistry, Genetics and Molecular Biology ,Article ,law.invention ,03 medical and health sciences ,Exon ,0302 clinical medicine ,law ,Huntingtin Protein ,Humans ,Protein Interaction Maps ,030304 developmental biology ,Polyproline helix ,0303 health sciences ,Multidisciplinary ,Intrinsically disordered proteins ,Chemistry ,food and beverages ,Neurodegenerative Diseases ,General Chemistry ,Molecular conformation ,Huntington Disease ,Toxicity ,Recombinant DNA ,Biophysics ,Protein aggregation ,Peptides ,030217 neurology & neurosurgery - Abstract
The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease., Huntingtin exon-1 (HTTex1) consists of a N-terminal N17 domain, the disease causing polyQ domain and a C-terminal proline-rich domain (PRD). Here, the authors combine electron paramagnetic resonance (EPR), solid-state NMR with other biophysical method to characterise the structural differences of various HTTex1 fibril types with different toxicity and find that the dynamics and entanglement of the PRD domain differs among them and that the HTTex1 fibrils can be interconverted.
- Published
- 2019