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

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. Arbing, Brent L. Nannenga, Johan Hattne, Julian Whitelegge, Aaron S. Brewster, Marc Messerschmidt, Sébastien Boutet, Nicholas K. Sauter, Tamir Gonen () and David S. Eisenberg ()
Additional contact information
Jose A. Rodriguez: Howard Hughes Medical Institute, UCLA-DOE Institute
Magdalena I. Ivanova: Howard Hughes Medical Institute, UCLA-DOE Institute
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
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
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

Nature, 2015, vol. 525, issue 7570, 486-490

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15368

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