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Protein Science (2008), 17:855-868. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Structural effects of Parkinson's disease linked DJ-1 mutations

Gaetano Malgieri and David Eliezer

Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, New York 10021, USA

(RECEIVED December 17, 2007; FINAL REVISION February 12, 2008; ACCEPTED February 18, 2008)

Mutations in the protein DJ-1 are associated with familial forms of Parkinson's disease, indicating that DJ-1 may be involved in pathways related to the etiology of this disorder. Here we have used solution state NMR and circular dichroism spectroscopies to evaluate the extent of structural perturbations associated with five different Parkinson's disease linked DJ-1mutations: L166P, E64D, M26I, A104T, and D149A. Comparison of the data with those obtained for the wild-type protein shows that the L166P mutation leads to severe and global destabilization and unfolding of the protein structure, while the structure of the E64D mutation, as expected, is nearly unperturbed. Interestingly, the remaining three mutants all show different degrees of structural perturbation, which are accompanied by a reduction in the thermodynamic stability of the protein. The observed structural and thermodynamic differences are likely to underlie any functional variations between these mutants and the wild type, which in turn are likely responsible for the pathogenicity of these mutations.

Keywords: Parkinson's disease; DJ-1; protein structure; protein stability; NMR; circular dichroism


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