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.
Olzmann
James A
JA
Departments of Pharmacology, Biochemistry, and Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322-3090, USA.
Brown
Keith
K
Wilkinson
Keith D
KD
Rees
Howard D
HD
Huai
Qing
Q
Ke
Hengming
H
Levey
Allan I
AI
Li
Lian
L
Chin
Lih-Shen
LS
D000595:Amino Acid Sequence; D000906:Antibodies / Q000276:immunology; D001923:Brain Chemistry; D002384:Catalysis; D003546:Cysteine Endopeptidases / Q000378:metabolism; D019281:Dimerization; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020734:Parkinsonian Disorders / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex; D000071617:Protein Deglycase DJ-1; D017510:Protein Folding; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D000906:Antibodies; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex