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  Photocontrol of the β-Hairpin polypeptide structure through an optimized azobenzene-based amino acid analogue

Parlato, R., Volarić, J., Lasorsa, A., Bagherpoor Helabad, M., Kobauri, P., Jain, G., et al. (2024). Photocontrol of the β-Hairpin polypeptide structure through an optimized azobenzene-based amino acid analogue. Journal of the American Chemical Society, 146(3), 2062-2071. doi:10.1021/jacs.3c11155.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000E-4DF3-A Version Permalink: https://hdl.handle.net/21.11116/0000-000E-4DF4-9
Genre: Journal Article

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 Creators:
Parlato, Raffaella, Author
Volarić, Jana, Author
Lasorsa, Alessia, Author
Bagherpoor Helabad, Mahdi1, Author
Kobauri, Piermichele, Author
Jain, Greeshma, Author
Miettinen, Markus S., Author
Feringa, Ben L., Author
Szymanski, Wiktor, Author
van der Wel, Patrick C. A., Author
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1Markus Miettinen, Theorie & Bio-Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_3070372              

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 Abstract: A family of neurodegenerative diseases, including Huntington’s disease (HD) and spinocerebellar ataxias, are associated with an abnormal polyglutamine (polyQ) expansion in mutant proteins that become prone to form amyloid-like aggregates. Prior studies have suggested a key role for β-hairpin formation as a driver of nucleation and aggregation, but direct experimental studies have been challenging. Toward such research, we set out to enable spatiotemporal control over β-hairpin formation by the introduction of a photosensitive β-turn mimic in the polypeptide backbone, consisting of a newly designed azobenzene derivative. The reported derivative overcomes the limitations of prior approaches associated with poor photochemical properties and imperfect structural compatibility with the desired β-turn structure. A new azobenzene-based β-turn mimic was designed, synthesized, and found to display improved photochemical properties, both prior and after incorporation into the backbone of a polyQ polypeptide. The two isomers of the azobenzene-polyQ peptide showed different aggregate structures of the polyQ peptide fibrils, as demonstrated by electron microscopy and solid-state NMR (ssNMR). Notably, only peptides in which the β-turn structure was stabilized (azobenzene in the cis configuration) closely reproduced the spectral fingerprints of toxic, β-hairpin-containing fibrils formed by mutant huntingtin protein fragments implicated in HD. These approaches and findings will enable better deciphering of the roles of β-hairpin structures in protein aggregation processes in HD and other amyloid-related neurodegenerative diseases.

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Language(s): eng - English
 Dates: 2024-01-242024
 Publication Status: Issued
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 Identifiers: DOI: 10.1021/jacs.3c11155
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Title: Journal of the American Chemical Society
  Other : JACS
  Abbreviation : J. Am. Chem. Soc.
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 146 (3) Sequence Number: - Start / End Page: 2062 - 2071 Identifier: ISSN: 0002-7863