Simulation and modeling of synuclein-based 'protofibril' structures: as a means of understanding the molecular basis of Parkinson's disease

The protein α-synuclein (aS) is a 140 amino acid cytosolic protein of unknown function expressed abundantly in neurons and is associated with both environmentally induced and inherited forms of Parkinson's disease, the neurological disorder caused by progressive death of dopaminergic neurons in...

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Bibliographic Details
Published in:Journal of physics. Conference series 2008-07, Vol.125 (1), p.012056
Main Authors: Tsigelny, I F, Sharikov, Y, Miller, M A, Masliah, E
Format: Article
Language:English
Subjects:
Amino acids
Binding
Folding
Membranes
Modelling
Neurological diseases
Neurons
Parkinson's disease
Physics
Proteins
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Summary:The protein α-synuclein (aS) is a 140 amino acid cytosolic protein of unknown function expressed abundantly in neurons and is associated with both environmentally induced and inherited forms of Parkinson's disease, the neurological disorder caused by progressive death of dopaminergic neurons in the substantia nigra. Here we demonstrate that aS aggregation leads to protofibril formation that accompanies aS binding to membranes. The specific surfaces of aS that bind to membranes are likely developed during the folding maturation process, where the 3D combinations of amino acids that are bound to these surfaces are very specific. Using molecular modeling and simulation technique, we elucidate the folding pathway of aS into protofibril structures and its configurations that bind to membranes. These membrane-binding surfaces can be targeted with pharmaceutical intervention for dissolution.
ISSN:1742-6596
1742-6588
1742-6596
DOI:10.1088/1742-6596/125/1/012056