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  NFGAIL Amyloid Oligomers: The Onset of Beta-Sheet Formation and the Mechanism for Fibril Formation

Hoffmann, W., Folmert, K., Moschner, J., Huang, X., von Berlepsch, H., Koksch, B., et al. (2017). NFGAIL Amyloid Oligomers: The Onset of Beta-Sheet Formation and the Mechanism for Fibril Formation. Journal of the American Chemical Society. doi:10.1021/jacs.7b09510.

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 Creators:
Hoffmann, Waldemar1, 2, Author           
Folmert, Kristin1, Author
Moschner, Johann1, Author
Huang, Xing3, Author           
von Berlepsch, Hans1, Author
Koksch, Beate1, Author
Bowers, Michael T.4, Author
Helden, Gert von2, Author           
Pagel, Kevin1, Author
Affiliations:
1Freie Universität Berlin, Institute of Chemistry and Biochemistry - Organic Chemistry, Takustr. 3, 14195 Berlin, Germany, ou_persistent22              
2Molecular Physics, Fritz Haber Institute, Max Planck Society, ou_634545              
3Inorganic Chemistry, Fritz Haber Institute, Max Planck Society, ou_24023              
4Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States, ou_persistent22              

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 Abstract: The hexapeptide NFGAIL is a highly amyloidogenic peptide, derived from the human islet amyloid polypeptide (hIAPP). Recent investigations indicate that presumably soluble hIAPP oligomers are one of the cytotoxic species in type II diabetes. Here we use thioflavin T staining, transmission electron microscopy, as well as ion mobility-mass spectrometry coupled to infrared (IR) spectroscopy to study the amyloid formation mechanism and the quaternary and secondary structure of soluble NFGAIL oligomers. Our data reveal that at neutral pH NFGAIL follows a nucleation dependent mechanism to form amyloid fibrils. During the lag phase, highly polydisperse, polymorph, and compact oligomers (oligomer number n = 2–13) as well as extended intermediates (n = 4–11) are present. IR secondary structural analysis reveals that compact conformations adopt turn-like structures, whereas extended oligomers exhibit a significant amount of β-sheet content. This agrees well with previous molecular dynamic simulations and provides direct experimental evidence that unordered off-pathway NFGAIL aggregates up to the size of at least the 13-mer as well as partially folded β-sheet containing oligomers are coexisting.

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Language(s): eng - English
 Dates: 2017-09-122017-12-13
 Publication Status: Published online
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/jacs.7b09510
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Title: Journal of the American Chemical Society
  Other : J. Am. Chem. Soc.
  Abbreviation : JACS
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0002-7863
CoNE: https://pure.mpg.de/cone/journals/resource/954925376870