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  Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein

Bertoncini, C. W., Jung, Y. S., Fernandez, C. O., Hoyer, W., Griesinger, C., Jovin, T. M., et al. (2005). Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1430-1435. Retrieved from http://www.pnas.org/content/102/5/1430.full.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0012-EA11-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-7F09-3
Genre: Journal Article

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 Creators:
Bertoncini, C. W.1, Author              
Jung, Y. S.2, Author              
Fernandez, C. O.3, Author
Hoyer, W.1, Author              
Griesinger, C.2, Author              
Jovin, T. M.1, Author              
Zweckstetter, M.4, Author              
Affiliations:
1Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society, ou_578628              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
3Max Planck Society, ou_persistent13              
4Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: α-synuclein, αS; RDC; residual dipolar coupling; PRE; paramagnetic relaxation enhancement; alpha-synuclein; amyloid; fibrillation; Parkinson’s disease
 Abstract: 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.

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Language(s): eng - English
 Dates: 2005-01-262005-02-01
 Publication Status: Published in print
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 Rev. Method: Peer
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 102 (5) Sequence Number: - Start / End Page: 1430 - 1435 Identifier: -