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  Architecture of polyglutamine-containing fibrils from time-resolved fluorescence decay

Röthlein, C., Miettinen, M. S., Borwankar, T., Bürger, J., Mielke, T., Kumke, M. U., et al. (2014). Architecture of polyglutamine-containing fibrils from time-resolved fluorescence decay. The Journal of Biological Chemistry, 289(39), 26817-26828. doi:10.1074/jbc.M114.581991.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-B3C4-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-B3C5-4
Genre: Journal Article

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© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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 Creators:
Röthlein, Christoph1, Author
Miettinen, Markus S. 2, Author
Borwankar, Tejas1, Author
Bürger, Jörg3, 4, Author              
Mielke, Thorsten3, 4, Author              
Kumke, Michael U., Author
Ignatova, Zoya 1, Author
Affiliations:
1Institute of Biochemistry and Biologie and Institute of Chemistry, University of Potsdam, 14467 Potsdam, ou_persistent22              
2Department of Theory of Biological Soft Matter Systems, Institute of Theoretical Physics, Free University Berlin, 14195 Berlin, ou_persistent22              
3Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
4Institut für Medizinische Physik und Biophysik, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, ou_persistent22              

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Free keywords: Amyloid; Computer Modeling; Fluorescence; Fluorescence Resonance Energy Transfer (FRET); Polyglutamine
 Abstract: The disease risk and age of onset of Huntington disease (HD) and nine other repeat disorders strongly depend on the expansion of CAG repeats encoding consecutive polyglutamines (polyQ) in the corresponding disease protein. PolyQ length-dependent misfolding and aggregation are the hallmarks of CAG pathologies. Despite intense effort, the overall structure of these aggregates remains poorly understood. Here, we used sensitive time-dependent fluorescent decay measurements to assess the architecture of mature fibrils of huntingtin (Htt) exon 1 implicated in HD pathology. Varying the position of the fluorescent labels in the Htt monomer with expanded 51Q (Htt51Q) and using structural models of putative fibril structures, we generated distance distributions between donors and acceptors covering all possible distances between the monomers or monomer dimensions within the polyQ amyloid fibril. Using Monte Carlo simulations, we systematically scanned all possible monomer conformations that fit the experimentally measured decay times. Monomers with four-stranded 51Q stretches organized into five-layered β-sheets with alternating N termini of the monomers perpendicular to the fibril axis gave the best fit to our data. Alternatively, the core structure of the polyQ fibrils might also be a zipper layer with antiparallel four-stranded stretches as this structure showed the next best fit. All other remaining arrangements are clearly excluded by the data. Furthermore, the assessed dimensions of the polyQ stretch of each monomer provide structural evidence for the observed polyQ length threshold in HD pathology. Our approach can be used to validate the effect of pharmacological substances that inhibit or alter amyloid growth and structure.

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Language(s): eng - English
 Dates: 2014-08-042014-09-26
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M114.581991
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Title: The Journal of Biological Chemistry
  Other : JBC
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: - Volume / Issue: 289 (39) Sequence Number: - Start / End Page: 26817 - 26828 Identifier: ISSN: 0021-9258
CoNE: /journals/resource/954925410826_1