Mechanism of copper(II)-induced misfolding of Parkinson's disease protein.

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Rose F, Hodak M, Bernholc J

Mechanism of copper(II)-induced misfolding of Parkinson's disease protein.

Sci Rep. 2011;1:11. doi: 10.1038/srep00011. Epub 2011 Jun 14.

PubMed ID

22355530 [ View in PubMed

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Abstract

alpha-synuclein (aS) is a natively unfolded pre-synaptic protein found in all Parkinson's disease patients as the major component of fibrillar plaques. Metal ions, and especially Cu(II), have been demonstrated to accelerate aggregation of aS into fibrillar plaques, the precursors to Lewy bodies. In this work, copper binding to aS is investigated by a combination of quantum and molecular mechanics simulations. Starting from the experimentally observed attachment site, several optimized structures of Cu-binding geometries are examined. The most energetically favorable attachment results in significant allosteric changes, making aS more susceptible to misfolding. Indeed, an inverse kinematics investigation of the configuration space uncovers a dynamically stable beta-sheet conformation of Cu-aS that serves as a nucleation point for a second beta-strand. Based on these findings, we propose an atomistic mechanism of copper-induced misfolding of aS as an initial event in the formation of Lewy bodies and thus in PD pathogenesis.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Copper	Alpha-synuclein	Protein	Humans	Unknown	Not Available	Details