期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 43, 页码 17797-17802出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1113260108
关键词
dynamic structure; helical; Parkinson's disease; NMR; heteronuclear single-quantum coherence
资金
- Michael J. Fox Foundation
- Indiana University School of Medicine
- Fidelity Biosciences Research Initiative
- Ellison Medical Foundation
- McKnight Endowment for Neuroscience
- National Institutes of Health, National Institute on Aging
A heterologously expressed form of the human Parkinson disease-associated protein alpha-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of alpha-helices in the first 100 N-terminal residues of the 140-residue alpha-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated hairpin structure of alpha-synuclein.
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