Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 16, Pages 5796-5801Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1401587111
Keywords
Huntington disease; isotope dilution; antiparallel beta-sheets; two-dimensional infrared spectroscopy
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Funding
- National Science Foundation [DGE-0718123, CHE-0840494, CBET-1264021]
- National Institutes of Health [DK79895, DK088184]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1264021] Funding Source: National Science Foundation
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Polyglutamine (polyQ) sequences are found in a variety of proteins, and mutational expansion of the polyQ tract is associated with many neurodegenerative diseases. We study the amyloid fibril structure and aggregation kinetics of K(2)Q(24)K(2)W, a model polyQ sequence. Two structures have been proposed for amyloid fibrils formed by polyQ peptides. By forming fibrils composed of both C-12 and C-13 monomers, made possible by protein expression in Escherichia coli, we can restrict vibrational delocalization to measure 2D IR spectra of individual monomers within the fibrils. The spectra are consistent with a beta-turn structure in which each monomer forms an antiparallel hairpin and donates two strands to a single beta-sheet. Calculated spectra from atomistic molecular-dynamics simulations of the two proposed structures confirm the assignment. No spectroscopically distinct intermediates are observed in rapid-scan 2D IR kinetics measurements, suggesting that aggregation is highly cooperative. Although 2D IR spectroscopy has advantages over linear techniques, the isotope-mixing strategy will also be useful with standard Fourier transform IR spectroscopy.
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