Release of Long-Range Tertiary Interactions Potentiates Aggregation of Natively Unstructured α-Synuclein

In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein α-synuclein (αS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, αS...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 5; pp. 1430 - 1435
Main Authors:	Bertoncini, Carlos W., Jung, Young-Sang, Fernandez, Claudio O., Hoyer, Wolfgang, Griesinger, Christian, Jovin, Thomas M., Zweckstetter, Markus, Petsko, Gregory A.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 01-02-2005 National Acad Sciences
Series:	From the Cover
Subjects:	Aggregation alpha-Synuclein Amides Anisotropy Binding Sites Biochemistry Biological Sciences Biophysics Cloning, Molecular Escherichia coli Fibrillation Humans Macromolecular Substances Magnetic Resonance Spectroscopy Models, Molecular Nerve Tissue Proteins - chemistry Parkinson disease Parkinson's disease Polyamines Protein Conformation Protein folding Protein Structure, Tertiary Proteins Protons Ratios Recombinant Proteins - chemistry Spin labels Synucleins Thermodynamics
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Summary:	In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein α-synuclein (αS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, αS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric αS assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerization and aggregation. The autoinhibitory conformations fluctuate in the range of nanoseconds to microseconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and/or temperature increase, conditions that induce aggregation in vitro, release this inherent tertiary structure, leading to a completely unfolded conformation that associates readily. Stabilization of the native, autoinhibitory structure of αS constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 This paper was submitted directly (Track II) to the PNAS office. Edited by Gregory A. Petsko, Brandeis University, Waltham, MA To whom correspondence should be addressed. E-mail: mzwecks@gwdg.de. Abbreviations: αS, α-synuclein; PD, Parkinson's disease; RDC, residual dipolar coupling; PRE, paramagnetic relaxation enhancement; MTSL, 1-oxy-2,2,5,5-tetramethyl-d-pyrroline-3-methyl)-methanethiosulfonate; HSQC, heteronuclear single quantum coherence; NAC, non-Aβ component of Alzheimer's disease amyloid.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0407146102