Two-dimensional IR spectroscopy and isotope labeling defines the pathway of amyloid formation with residue-specific resolution
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- Two-dimensional IR spectroscopy and isotope labeling defines the pathway of amyloid formation with residue-specific resolution
- Shim, Sang-Hee; Gupta, Ruchi; Ling, Yun L.; Strasfeld, David B.; Raleigh, Daniel P.; Zanni, Martin T.
- Aggregation; Amylin; Fibers; Human islet amyloid polypeptide; Nucleation
- Issue Date
- NATL ACAD SCIENCES
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.106, no.16, pp.6614 - 6619
- There is considerable interest in uncovering the pathway of amyloid formation because the toxic properties of amyloid likely stems from prefibril intermediates and not the fully formed fibrils. Using a recently invented method of collecting 2-dimensional infrared spectra and site-specific isotope labeling, we have measured the development of secondary structures for 6 residues during the aggregation process of the 37-residue polypeptide associated with type 2 diabetes, the human islet amyloid polypeptide (hIAPP). By monitoring the kinetics at 6 different labeled sites, we find that the peptides initially develop well-ordered structure in the region of the chain that is close to the ordered loop of the fibrils, followed by formation of the 2 parallel β-sheets with the N-terminal β-sheet likely forming before the C-terminal sheet. This experimental approach provides a detailed view of the aggregation pathway of hIAPP fibril formation as well as a general methodology for studying other amyloid forming proteins without the use of structure-perturbing labels.
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