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Membrane-bound ?-synuclein interacts with glucocerebrosidase and inhibits enzyme activity.


ABSTRACT: Mutations in GBA, the gene encoding glucocerebrosidase, the lysosomal enzyme deficient in Gaucher disease increase the risk for developing Parkinson disease. Recent research suggests a relationship between glucocerebrosidase and the Parkinson disease-related amyloid-forming protein, ?-synuclein; however, the specific molecular mechanisms responsible for association remain elusive. Previously, we showed that ?-synuclein and glucocerebrosidase interact selectively under lysosomal conditions, and proposed that this newly identified interaction might influence cellular levels of ?-synuclein by either promoting protein degradation and/or preventing aggregation. Here, we demonstrate that membrane-bound ?-synuclein interacts with glucocerebrosidase, and that this complex formation inhibits enzyme function. Using site-specific fluorescence and Förster energy transfer probes, we mapped the protein-enzyme interacting regions on unilamellar vesicles. Our data suggest that on the membrane surface, the glucocerebrosidase-?-synuclein interaction involves a larger ?-synuclein region compared to that found in solution. In addition, ?-synuclein acts as a mixed inhibitor with an apparent IC(50) in the submicromolar range. Importantly, the membrane-bound, ?-helical form of ?-synuclein is necessary for inhibition. This glucocerebrosidase interaction and inhibition likely contribute to the mechanism underlying GBA-associated parkinsonism.

SUBMITTER: Yap TL 

PROVIDER: S-EPMC3552326 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Membrane-bound α-synuclein interacts with glucocerebrosidase and inhibits enzyme activity.

Yap Thai Leong TL   Velayati Arash A   Sidransky Ellen E   Lee Jennifer C JC  

Molecular genetics and metabolism 20121128 1


Mutations in GBA, the gene encoding glucocerebrosidase, the lysosomal enzyme deficient in Gaucher disease increase the risk for developing Parkinson disease. Recent research suggests a relationship between glucocerebrosidase and the Parkinson disease-related amyloid-forming protein, α-synuclein; however, the specific molecular mechanisms responsible for association remain elusive. Previously, we showed that α-synuclein and glucocerebrosidase interact selectively under lysosomal conditions, and p  ...[more]

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