Publication Date:
2015-09-10
Description:
The protein alpha-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 alpha-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 A 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 beta-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length alpha-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 alpha-synuclein fibril, presenting opportunities for the design of inhibitors of alpha-synuclein fibrils.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rodriguez, Jose A -- Ivanova, Magdalena I -- Sawaya, Michael R -- Cascio, Duilio -- Reyes, Francis E -- Shi, Dan -- Sangwan, Smriti -- Guenther, Elizabeth L -- Johnson, Lisa M -- Zhang, Meng -- Jiang, Lin -- Arbing, Mark A -- Nannenga, Brent L -- Hattne, Johan -- Whitelegge, Julian -- Brewster, Aaron S -- Messerschmidt, Marc -- Boutet, Sebastien -- Sauter, Nicholas K -- Gonen, Tamir -- Eisenberg, David S -- 1R01-AG029430/AG/NIA NIH HHS/ -- AG016570/AG/NIA NIH HHS/ -- GM095887/GM/NIGMS NIH HHS/ -- GM102520/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM095887/GM/NIGMS NIH HHS/ -- R01 GM102520/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 24;525(7570):486-90. doi: 10.1038/nature15368. Epub 2015 Sep 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, UCLA-DOE Institute, Departments of Biological Chemistry and Chemistry and Biochemistry, Box 951570, UCLA, Los Angeles, California 90095-1570, USA. ; Howard Hughes Medical Institute, Janelia Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA. ; Box 42, NPI-Semel Institute, 760 Westwood Plaza, UCLA, Los Angeles, California 90024, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26352473" target="_blank"〉PubMed〈/a〉
Keywords:
Amyloid/chemistry
;
Cryoelectron Microscopy
;
Electrons
;
Humans
;
Lewy Bodies/chemistry
;
Models, Molecular
;
Nanoparticles/*chemistry/*toxicity
;
Parkinson Disease
;
Protein Structure, Tertiary
;
Scattering, Radiation
;
alpha-Synuclein/*chemistry/*toxicity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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