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          Institute: MPI für biophysikalische Chemie     Collection: Molekulare Biologie (Dr. Thomas M. Jovin)     Display Documents



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ID: 207200.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein
Authors:Bertoncini, C. W.; Jung, Y. S.; Fernandez, C. O.; Hoyer, W.; Griesinger, C.; Jovin, T. M.; Zweckstetter, M.
Language:English
Date of Publication (YYYY-MM-DD):2005-02-01
Title of Journal:Proceedings of the National Academy of Sciences of the United States of America
Volume:102
Issue / Number:5
Start Page:1430
End Page:1435
Sequence Number of Article:doi:10.1073/pnas.0407146102
Review Status:Peer-review
Audience:Not Specified
Abstract / Description: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.
Free Keywords:α-synuclein, αS; RDC; residual dipolar coupling; PRE; paramagnetic relaxation enhancement; alpha-synuclein; amyloid; fibrillation; Parkinson’s disease
Last Change of the Resource (YYYY-MM-DD):2005-01-26
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
MPI für biophysikalische Chemie/Abt. Christian Griesinger / 030
MPI für biophysikalische Chemie/AG Markus Zweckstetter
External Affiliations:Instituto de Biología Molecular y Celular de Rosario, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
Identifiers:URL:http://www.pnas.org/content/102/5/1430.full
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