Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 138, Issue 13, Pages 4458-4467Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.5b13261
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Funding
- National Science Foundation (NSF) [CHE-1507840]
- UCI Training Program in Chemical and Structural Biology [T32 GM108561]
- National Institutes of Health, National Institute of General Medical Sciences
- Howard Hughes Medical Institute
- U.S. Department of Energy [DE-AC02-05CH11231]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1507840] Funding Source: National Science Foundation
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Oligomeric assemblies of the protein alpha-synuclein are thought to cause neurodegeneration in Parkinson's disease and related synucleinopathies. Characterization of alpha-synuclein oligomers at high resolution is an outstanding challenge in the field of structural biology. The absence of high-resolution structures of oligomers formed by alpha-synuclein impedes understanding the synucleinopathies at the molecular level. This paper reports the X-ray crystallographic structure of oligomers formed by a peptide derived from residues 36-55 of alpha-synuclein. The peptide 1a adopts a beta-hairpin structure, which assembles in a hierarchical fashion. Three beta-hairpins assemble to form a triangular trimer. Three copies of the triangular trimer assemble to form a basket-shaped nonamer. Two nonamers pack to form an octadecamer. Molecular modeling suggests that full-length alpha-synuclein may also be able to assemble in this fashion. Circular dichroism spectroscopy demonstrates that peptide la interacts with anionic lipid bilayer membranes, like oligomers of full-length alpha-synuclein. LDH and MTT assays demonstrate that peptide 1a is toxic toward SH-SYSY cells. Comparison of peptide 1a to homologues suggests that this toxicity results from nonspecific interactions with the cell membrane. The oligomers formed by peptide 1a are fundamentally different than the proposed models of the fibrils formed by alpha-synuclein and suggest that alpha-Syn(36-55), rather than the NAC, may nucleate oligomer formation.
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