Unknown

Dataset Information

0

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


ABSTRACT: In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein alpha-synuclein (alphaS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, alphaS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric alphaS 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 micro-seconds 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 alphaS constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.

SUBMITTER: Bertoncini CW 

PROVIDER: S-EPMC547830 | biostudies-other | 2005 Feb

REPOSITORIES: biostudies-other

altmetric image

Publications

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

Bertoncini Carlos W CW   Jung Young-Sang YS   Fernandez Claudio O CO   Hoyer Wolfgang W   Griesinger Christian C   Jovin Thomas M TM   Zweckstetter Markus M  

Proceedings of the National Academy of Sciences of the United States of America 20050125 5


In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein alpha-synuclein (alphaS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, alphaS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric alphaS assumes conformations that are stabilized by long-ran  ...[more]

Similar Datasets

| S-EPMC4458405 | biostudies-literature
| S-EPMC2519050 | biostudies-literature
| S-EPMC526467 | biostudies-literature
| S-EPMC8460662 | biostudies-literature
| S-EPMC4138985 | biostudies-literature
| S-EPMC6117395 | biostudies-literature
| S-EPMC8558257 | biostudies-literature
| S-EPMC4609965 | biostudies-literature
| S-EPMC7460339 | biostudies-literature
| S-EPMC6100766 | biostudies-literature