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The 1.1-Å Resolution Crystal Structure of DJ-1, the Protein Mutated in Autosomal Recessive Early Onset Parkinson's Disease

Mutations in DJ-1, a human gene with homologues in organisms from all kingdoms of life, have been shown to be associated with autosomal recessive, early onset Parkinson's disease (PARK7). We report here the three-dimensional structure of the DJ-1 protein, determined at a resolution of 1.1 Å by...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2003-08, Vol.100 (16), p.9256-9261
Main Authors: Wilson, Mark A., Collins, Jennifer L., Hod, Yaacov, Ringe, Dagmar, Petsko, Gregory A.
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Collins, Jennifer L.
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Petsko, Gregory A.
description Mutations in DJ-1, a human gene with homologues in organisms from all kingdoms of life, have been shown to be associated with autosomal recessive, early onset Parkinson's disease (PARK7). We report here the three-dimensional structure of the DJ-1 protein, determined at a resolution of 1.1 Å by x-ray crystallography. The chain fold of DJ-1 resembles those of a bacterial protein, PfpI, that has been annotated as a cysteine protease, and of a domain of a bacterial catalase whose role in the activity of that enzyme is uncertain. In contrast to PfpI, a hexameric protein whose oligomeric structure is essential for its putative proteolytic activity, DJ-1 is a dimer with completely different intersubunit contacts. The proposed catalytic triad of PfpI is absent from the corresponding region of the structure of DJ-1, and biochemical assays fail to detect any protease activity for purified DJ-1. A highly conserved cysteine residue, which is catalytically essential in homologues of DJ-1, shows an extreme sensitivity to radiation damage and may be subject to other forms of oxidative modification as well. The structure suggests that the loss of function caused by the Parkinson's-associated mutation L166P in DJ-1 is due to destabilization of the dimer interface. Taken together, the crystal structure of human DJ-1 plus other observations suggest the possible involvement of this protein in the cellular oxidative stress response and a general etiology of neurodegenerative diseases.
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The structure suggests that the loss of function caused by the Parkinson's-associated mutation L166P in DJ-1 is due to destabilization of the dimer interface. Taken together, the crystal structure of human DJ-1 plus other observations suggest the possible involvement of this protein in the cellular oxidative stress response and a general etiology of neurodegenerative diseases.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12855764</pmid><doi>10.1073/pnas.1133288100</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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source JSTOR Archival Journals and Primary Sources Collection; PubMed Central
subjects Archaeal Proteins
Biochemistry
Biological Sciences
Catalysis
Chromatography, Gel
Crystal structure
Crystallography, X-Ray
Cysteine - chemistry
Dimerization
Dimers
Endopeptidases - chemistry
Escherichia coli - metabolism
Genes, Recessive
Genetic mutation
Intracellular Signaling Peptides and Proteins
Models, Molecular
Monomers
Mutation
Neurons
Oncogene Proteins - chemistry
Oncogene Proteins - genetics
Oxidative Stress
Parkinson disease
Parkinson Disease - genetics
Peptide Hydrolases - chemistry
Protein Conformation
Protein Deglycase DJ-1
Protein Structure, Tertiary
Proteins
Reactive oxygen species
Recombinant Fusion Proteins - chemistry
title The 1.1-Å Resolution Crystal Structure of DJ-1, the Protein Mutated in Autosomal Recessive Early Onset Parkinson's Disease
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