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Structure of the toxic core of α-synuclein from invisible crystals

Author

Listed:
  • Jose A. Rodriguez

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Magdalena I. Ivanova

    (Howard Hughes Medical Institute, UCLA-DOE Institute
    †Present addresses: Department of Neurology and Program of Biophysics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA (M.I.I.); Department of Neurology, UCLA, Los Angeles, California 90095, USA (L.J.); National Science Foundation BioXFEL Science and Technology Center, Buffalo, New York 14203, USA (M.M.).)

  • Michael R. Sawaya

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Duilio Cascio

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Francis E. Reyes

    (Howard Hughes Medical Institute, Janelia Research Campus)

  • Dan Shi

    (Howard Hughes Medical Institute, Janelia Research Campus)

  • Smriti Sangwan

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Elizabeth L. Guenther

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Lisa M. Johnson

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Meng Zhang

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Lin Jiang

    (Howard Hughes Medical Institute, UCLA-DOE Institute
    †Present addresses: Department of Neurology and Program of Biophysics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA (M.I.I.); Department of Neurology, UCLA, Los Angeles, California 90095, USA (L.J.); National Science Foundation BioXFEL Science and Technology Center, Buffalo, New York 14203, USA (M.M.).)

  • Mark A. Arbing

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

  • Brent L. Nannenga

    (Howard Hughes Medical Institute, Janelia Research Campus)

  • Johan Hattne

    (Howard Hughes Medical Institute, Janelia Research Campus)

  • Julian Whitelegge

    (Box 42, NPI-Semel Institute)

  • Aaron S. Brewster

    (Lawrence Berkeley National Laboratory)

  • Marc Messerschmidt

    (Linac Coherent Light Source, SLAC National Accelerator Laboratory
    †Present addresses: Department of Neurology and Program of Biophysics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA (M.I.I.); Department of Neurology, UCLA, Los Angeles, California 90095, USA (L.J.); National Science Foundation BioXFEL Science and Technology Center, Buffalo, New York 14203, USA (M.M.).)

  • Sébastien Boutet

    (Linac Coherent Light Source, SLAC National Accelerator Laboratory)

  • Nicholas K. Sauter

    (Lawrence Berkeley National Laboratory)

  • Tamir Gonen

    (Howard Hughes Medical Institute, Janelia Research Campus)

  • David S. Eisenberg

    (Howard Hughes Medical Institute, UCLA-DOE Institute)

Abstract

The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.

Suggested Citation

  • Jose A. Rodriguez & Magdalena I. Ivanova & Michael R. Sawaya & Duilio Cascio & Francis E. Reyes & Dan Shi & Smriti Sangwan & Elizabeth L. Guenther & Lisa M. Johnson & Meng Zhang & Lin Jiang & Mark A. , 2015. "Structure of the toxic core of α-synuclein from invisible crystals," Nature, Nature, vol. 525(7570), pages 486-490, September.
    • Handle: RePEc:nat:nature:v:525:y:2015:i:7570:d:10.1038_nature15368
    DOI: 10.1038/nature15368
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    Cited by:

    1. Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022. "Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Sabine M. Ulamec & Roberto Maya-Martinez & Emily J. Byrd & Katherine M. Dewison & Yong Xu & Leon F. Willis & Frank Sobott & George R. Heath & Patricija Oosten Hawle & Vladimir L. Buchman & Sheena E. R, 2022. "Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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