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

Rose, Frisco; Hodak, Miroslav; Bernholc, Jerzy

doi:10.1038/srep00011

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

Journal Article · Tue Jun 14 00:00:00 EDT 2011 · Scientific Reports

DOI:https://doi.org/10.1038/srep00011· OSTI ID:1564755

Rose, Frisco ^[1]; Hodak, Miroslav ^[1]; Bernholc, Jerzy ^[1]

North Carolina State Univ., Raleigh, NC (United States). Center for High Performance Simulation and Dept. of Physics

α-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 β-sheet conformation of Cu-aS that serves as a nucleation point for a second β-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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); North Carolina State University, Raleigh, NC (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: FG02-98ER45685

OSTI ID:: 1564755

Journal Information:: Scientific Reports, Vol. 1, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 60 works

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Interaction of Cu( i ) with the Met-X ₃ -Met motif of alpha-synuclein: binding ligands, affinity and structural features Gentile, Iñaki; Garro, Hugo A.; Delgado Ocaña, Susana Metallomics, Vol. 10, Issue 10 https://doi.org/10.1039/c8mt00232k	journal	January 2018
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