A soluble α-synuclein construct forms a dynamic tetramer
Open accessAbstract
A heterologously expressed form of the human Parkinson disease-associated protein α-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 α-helices in the first 100 N-terminal residues of the 140-residue α-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 α-synuclein.
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In human brain lysates, human neuronal cultures, mouse models, and cell lines expressing familial PD αSyn mutations (A53T or E46K), a decrease in the tetramer:monomer ratio correlates with increased neurotoxicity.
“in human brain lysates, human neuronal cultures, mouse models, and in mouse/human/goat cell lines expressing familial PD αSyn mutations (A53T or E46K), a decrease in the tetramer:monomer ratio correlated to increased neurotoxicity”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [137]
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- Authors
- Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., Ju, S., Cookson, M. R., Asturias, F. J., Agar, J. N., Webb, B. N., Kang, C., Ringe, D., Petsko, G. A., Pochapsky, T. C., & Hoang, Q. Q.
- Affiliations
- Indiana University Indianapolis (US)
- Brandeis University (US)
- Scripps Research Institute (US)
- National Institutes of Health (US)
- Indiana University Bloomington (US)
- Washington State University (US)
- Brigham and Women's Hospital (US)
- Indiana University School of Medicine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-10-17
- Volume
- 108
- Issue
- 43
- Pages
- 17797-17802
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3203798
- OpenAlex
- W2077881833
- Cited by
- 478
- References
- 35
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 25 · 2023: 15 · 2022: 35 · 2021: 34 · 2020: 20 · 2019: 35 · 2018: 35 · 2017: 29 · 2016: 30 · 2015: 36 · 2014: 45 · 2013: 51 · 2012: 52
- FWCI
- 30.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM044191, R01GM067167)
- National Institute of Neurological Disorders and Stroke (R01NS065263)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, Parkinson's disease, protein oligomerization, N-terminal extension, alpha-helix, amphipathic helix, hydrophobic core, hairpin structure
- MeSH terms
- Circular Dichroism, Humans, Microscopy, Electron, Models, Molecular, Polymers, Protein Structure, Secondary, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Nuclear Magnetic Resonance, Biomolecular, alpha-Synuclein
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