Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function.

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.
Mesh Terms:
Amino Acid Sequence, Antibodies, Brain Chemistry, Catalysis, Cysteine Endopeptidases, Dimerization, Gene Expression, Green Fluorescent Proteins, Humans, Immunohistochemistry, Intracellular Signaling Peptides and Proteins, Luminescent Proteins, Molecular Sequence Data, Multienzyme Complexes, Mutation, Oncogene Proteins, Parkinsonian Disorders, Peptide Fragments, Polymerase Chain Reaction, Proteasome Endopeptidase Complex, Protein Folding, Recombinant Proteins, Structure-Activity Relationship, Transfection, Ubiquitin
J. Biol. Chem.
Date: Feb. 27, 2004
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