Abstract
Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Antibodies / immunology
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Brain Chemistry
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Catalysis
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Cysteine Endopeptidases / metabolism
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Dimerization
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Gene Expression
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Green Fluorescent Proteins
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Humans
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Immunohistochemistry
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins / genetics
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Molecular Sequence Data
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Multienzyme Complexes / metabolism
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Mutation*
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Oncogene Proteins / chemistry
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Oncogene Proteins / genetics*
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Oncogene Proteins / physiology
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Parkinsonian Disorders / genetics*
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Peptide Fragments / chemistry
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Peptide Fragments / immunology
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Polymerase Chain Reaction
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Proteasome Endopeptidase Complex
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Protein Deglycase DJ-1
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Protein Folding
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Recombinant Proteins
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Structure-Activity Relationship
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Transfection
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Ubiquitin / metabolism
Substances
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Antibodies
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins
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Multienzyme Complexes
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Oncogene Proteins
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Peptide Fragments
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Recombinant Proteins
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Ubiquitin
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Green Fluorescent Proteins
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PARK7 protein, human
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Protein Deglycase DJ-1
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex