Structural features and domain organization of huntingtin fibrils
| Autor: | Paul H. Patterson, Ralf Langen, Torsten Fischer, Charles W. Bugg, J. Mario Isas |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Protein Denaturation Huntingtin Amyloid Protein Conformation Nerve Tissue Proteins macromolecular substances Fibril Biochemistry law.invention Thioredoxins law mental disorders Humans Electron paramagnetic resonance Molecular Biology Polyproline helix Huntingtin Protein Chemistry Circular Dichroism Electron Spin Resonance Spectroscopy Cell Biology Site-directed spin labeling Exons Recombinant Proteins nervous system diseases Protein Structure Tertiary Crystallography Structural biology Domain (ring theory) Protein Structure and Folding Mutagenesis Site-Directed Peptides |
| Zdroj: | The Journal of biological chemistry. 287(38) |
| ISSN: | 1083-351X |
| Popis: | Misfolding and aggregation of huntingtin is one of the hallmarks of Huntington disease, but the overall structure of these aggregates and the mechanisms by which huntingtin misfolds remain poorly understood. Here we used site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy to study the structural features of huntingtin exon 1 (HDx1) containing 46 glutamine residues in its polyglutamine (polyQ) region. Despite some residual structuring in the N terminus, we find that soluble HDx1 is highly dynamic. Upon aggregation, the polyQ domain becomes strongly immobilized indicating significant tertiary or quaternary packing interactions. Analysis of spin-spin interactions does not show the close contact between same residues that is characteristic of the parallel, in-register structure commonly found in amyloids. Nevertheless, the same residues are still within 20 Å of each other, suggesting that polyQ domains from different molecules come into proximity in the fibrils. The N terminus has previously been found to take up a helical structure in fibrils. We find that this domain not only becomes structured, but that it also engages in tertiary or quaternary packing interactions. The existence of spin-spin interactions in this region suggests that such contacts could be made between N-terminal domains from different molecules. In contrast, the C-terminal domain is dynamic, contains polyproline II structure, and lacks pronounced packing interactions. This region must be facing away from the core of the fibrils. Collectively, these data provide new constraints for building structural models of HDx1 fibrils. |
| Databáze: | OpenAIRE |
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