Univ. of Illinois, Urbana, IL (United States). Dept. of Chemistry; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL
Univ. of Illinois, Urbana, IL (United States). Center for Biophysics and Quantitative Biology
Univ. of Illinois, Urbana, IL (United States). Dept. of Chemistry
Univ. of Pennsylvania, Philadelphia, PA (United States). School of Medicine. Dept. of Pathology and Lab. Medicine. Inst. on Aging. Center for Neurodegenerative Disease Research
Vanderbilt Univ., Nashville, TN (United States). Dept. of Biological Sciences. Center for Structural Biology
National Inst. of Health (NIH), Bethesda, MD (United States). Division of Computational Bioscience. Center for Information Technology
Queen Mary Univ. of London (United Kingdom). Dept. of Biological and Experimental Psychology. School of Biological and Chemical Sciences
Univ. of Illinois, Urbana, IL (United States). Dept. of Chemistry. Center for Biophysics and Quantitative Biology. Dept. of Biochemistry
Misfolded α-synuclein amyloid fibrils are the principal components of Lewy bodies and neurites, hallmarks of Parkinson's disease (PD). In this paper, we present a high-resolution structure of an α-synuclein fibril, in a form that induces robust pathology in primary neuronal culture, determined by solid-state NMR spectroscopy and validated by EM and X-ray fiber diffraction. Over 200 unique long-range distance restraints define a consensus structure with common amyloid features including parallel, in-register β-sheets and hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new orthogonal Greek-key topology. These characteristics contribute to the robust propagation of this fibril form, as supported by the structural similarity of early-onset-PD mutants. Finally, the structure provides a framework for understanding the interactions of α-synuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.
Tuttle, Marcus D., et al. "Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein." Nature Structural & Molecular Biology, vol. 23, no. 5, Mar. 2016. https://doi.org/10.1038/nsmb.3194
Tuttle, Marcus D., Comellas, Gemma, Nieuwkoop, Andrew J., Covell, Dustin J., Berthold, Deborah A., Kloepper, Kathryn D., Courtney, Joseph M., Kim, Jae K., Barclay, Alexander M., Kendall, Amy, Wan, William, Stubbs, Gerald, Schwieters, Charles D., Lee, Virginia M. Y., George, Julia M., & Rienstra, Chad M. (2016). Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nature Structural & Molecular Biology, 23(5). https://doi.org/10.1038/nsmb.3194
Tuttle, Marcus D., Comellas, Gemma, Nieuwkoop, Andrew J., et al., "Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein," Nature Structural & Molecular Biology 23, no. 5 (2016), https://doi.org/10.1038/nsmb.3194
@article{osti_1467083,
author = {Tuttle, Marcus D. and Comellas, Gemma and Nieuwkoop, Andrew J. and Covell, Dustin J. and Berthold, Deborah A. and Kloepper, Kathryn D. and Courtney, Joseph M. and Kim, Jae K. and Barclay, Alexander M. and Kendall, Amy and others},
title = {Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein},
annote = {Misfolded α-synuclein amyloid fibrils are the principal components of Lewy bodies and neurites, hallmarks of Parkinson's disease (PD). In this paper, we present a high-resolution structure of an α-synuclein fibril, in a form that induces robust pathology in primary neuronal culture, determined by solid-state NMR spectroscopy and validated by EM and X-ray fiber diffraction. Over 200 unique long-range distance restraints define a consensus structure with common amyloid features including parallel, in-register β-sheets and hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new orthogonal Greek-key topology. These characteristics contribute to the robust propagation of this fibril form, as supported by the structural similarity of early-onset-PD mutants. Finally, the structure provides a framework for understanding the interactions of α-synuclein with other proteins and small molecules, to aid in PD diagnosis and treatment.},
doi = {10.1038/nsmb.3194},
url = {https://www.osti.gov/biblio/1467083},
journal = {Nature Structural & Molecular Biology},
issn = {ISSN 1545-9993},
number = {5},
volume = {23},
place = {United States},
publisher = {Nature Publishing Group},
year = {2016},
month = {03}}
National Inst. of Health (NIH), Bethesda, MD (United States); Univ. of Illinois, Urbana, IL (United States); Univ. of Pennsylvania, Philadelphia, PA (United States); Vanderbilt Univ., Nashville, TN (United States)
Sponsoring Organization:
National Inst. of Health (NIH) (United States); National Science Foundation (NSF) (United States); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)