Structure of the toxic core of α-synuclein from invisible crystals.
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.
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Jose A
JA
Rodriguez
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Magdalena I
MI
Ivanova
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Michael R
MR
Sawaya
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Duilio
D
Cascio
Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA.
Francis E
FE
Reyes
Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA.
Dan
D
Shi
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Smriti
S
Sangwan
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Elizabeth L
EL
Guenther
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Lisa M
LM
Johnson
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Meng
M
Zhang
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Lin
L
Jiang
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
Mark A
MA
Arbing
Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA.
Brent L
BL
Nannenga
Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA.
Johan
J
Hattne
Box 42, NPI-Semel Institute, 760 Westwood Plaza, UCLA, Los Angeles, California 90024, USA.
Julian
J
Whitelegge
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Aaron S
AS
Brewster
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.
Marc
M
Messerschmidt
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.
Sébastien
S
Boutet
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Nicholas K
NK
Sauter
Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA.
Tamir
T
Gonen
Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA.
David S
DS
Eisenberg
D000682:Amyloid / Q000737:chemistry; D020285:Cryoelectron Microscopy; D004583:Electrons; D006801:Humans; D016631:Lewy Bodies / Q000737:chemistry; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity*; D010300:Parkinson Disease; D017434:Protein Structure, Tertiary; D012542:Scattering, Radiation; D051844:alpha-Synuclein / Q000737:chemistry* / Q000633:toxicity*
D000682:Amyloid; C497604:SNCA protein, human; D051844:alpha-Synuclein