Chaperone-like N-Methyl Peptide Inhibitors of Polyglutamine Aggregation
| Autor: | JohnMark Derryberry, Jennifer D. Lanning, Stephen C. Meredith, Andrew J. Hawk |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
chemistry.chemical_classification
Huntingtin biology Hydrogen bond Chemistry Peptide Surface Plasmon Resonance Fibril Methylation Biochemistry Protein Structure Secondary Article Huntington Disease Chaperone (protein) biology.protein Huntingtin Protein Side chain Biophysics Humans Peptides Polyproline helix |
| Zdroj: | Biochemistry. 49:7108-7118 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi1006095 |
| Popis: | Expanded polyglutamine (polyQ) tracts are responsible for at least nine neurodegenerative diseases, including Huntington’s Disease (HD). HD occurs when the polyQ domain of exon 1 of huntingtin protein expands beyond a threshold of approximately 35 residues (1), leading to polyQ aggregation (2-4). PolyQ proteins can form β-sheet rich fibrils (5, 6). In contrast to many other amyloids (7), polyQ domains have polar side chains, and both these and backbone atoms can form hydrogen bonds. Recent x-ray diffraction and solid-state NMR studies of the glutamine- and asparagine-rich yeast prion proteins Sup35p and Rnq1p show parallel in-register β-sheet segments, possibly separated by non-β-sheet bend structures in longer peptides (8, 9). Prefibrillar oligomers of β-amyloid are micelle-like and show β-sheet character (10). The structure of polyQ oligomers is not known, however; in contrast to oligomers of β-amyloid, the polar nature of poly Q makes it unlikely that they would be micelle-like. Large, prefibrillar “spheroids” of huntingtin also have been observed, and these acquire β-sheet structure as they mature into fibrils (11). We have recently shown that small, soluble oligomers of short polyQ peptides adopt a polyproline-II helix-like structure (12, 18), and thus the conversion to fibrils may require a transition from this structure to β-sheet. Inhibitors of protein and peptide aggregation are of value both as molecular probes of the aggregation pathway and as potential therapeutic agents (13-15). We have described peptidic inhibitors of β-amyloid, consisting of an aggregation domain in which alternate residues are N-methylated on backbone amides. Such inhibitors (e.g., Aβ16-20m) both inhibit fibril formation and disassemble preformed fibrils, by disrupting backbone hydrogen bonding (16, 17). In this paper, we describe what began as a comparison of N-methylation patterns in potential inhibitors of polyQ peptide aggregation. These studies, however, soon produced several surprising results, starting with the observation that side chain N-methylations alone yield the most effective inhibitors of all the permutations tested on short polyQ peptides. Subsequent experiments highlighted the importance of side chain interactions in polyQ aggregation, and showed that the inhibitors act through a mechanism reminiscent of chaperone proteins. We examined the most effective of these inhibitors in detail, and observed that it binds to a target polyQ peptide and inhibits its aggregation by forming a 1:1 stoichiometric complex. It inhibits not only nucleation, but also fibril extension, as shown by its ability to inhibit seeded fibril growth in which nucleation steps are bypassed. Furthermore, our data indicate that the effective inhibitors adopt a polyproline II conformation, and interact with a polyQ peptide only while it is also in the PPII conformation. These results suggest a more complex scheme for the polyglutamine aggregation pathway than has been appreciated previously. |
| Databáze: | OpenAIRE |
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