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, Sebastien Boutet, Nicholas K. Sauter, Tamir GonenDavid S. Eisenberg

Research output: Contribution to journalArticlepeer-review

283 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)486-490
Number of pages5
JournalNature
Volume525
Issue number7570
DOIs
StatePublished - Sep 24 2015

Bibliographical note

Funding Information:
Acknowledgements We thank C. Liu for supplying PC12 cells; APS staff for beam line help solving SubNACore: M. Capel, K. Rajashankar, N. Sukumar, J. Schuermann, I. Kourinov and F. Murphy at NECAT beam lines 24-ID at APS funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403) and the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank the LCLS injection staff support: S.Botha,R.ShoemanandI. Schlichting. A.S.B.andN.K.S.were supported byNIH grants GM095887 and GM102520 and by the Director, Office of Science, Department of Energy (DOE) under contract DE-AC02-05CH11231 for data-processing methods. This work was supported by the US Department of Energy Office of Science, Office of Biological and Environmental Research program under award number DE-FC02-02ER63421. We also acknowledge the award MCB-0958111 from the National Science Foundation, award 1R01-AG029430 from the National Institutes of Health, award NIH-AG016570 from Alzheimer’s Disease Research (ADRC) at UCLA, and HHMI for support. J.A.R. was supported by the Giannini Foundation.

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

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