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

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons59166

Hoffmann,  Waldemar
Freie Universität Berlin, Institute of Chemistry and Biochemistry - Organic Chemistry;
Molecular Physics, Fritz Haber Institute, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons39194

Huang,  Xing
Inorganic Chemistry, Fritz Haber Institute, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons21614

Helden,  Gert von
Molecular Physics, Fritz Haber Institute, Max Planck Society;

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Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002E-9F1D-5
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.