title: Dopamine-derived quinones affect the structure of the redox sensor DJ-1 through modifications at Cys-106 and Cys-53.
abstract: The physiological role of DJ-1, a protein involved in familial Parkinson disease is still controversial. One of the hypotheses proposed indicates a sensor role for oxidative stress, through oxidation of a conserved cysteine residue (Cys-106). The association of DJ-1 mutations with Parkinson disease suggests a loss of function, specific to dopaminergic neurons. Under oxidative conditions, highly reactive dopamine quinones (DAQs) can be produced, which can modify cysteine residues. In cellular models, DJ-1 was found covalently modified by dopamine. We analyzed the structural modifications induced on human DJ-1 by DAQs in vitro. We described the structural perturbations induced by DAQ adduct formation on each of the three cysteine residues of DJ-1 using specific mutants. Cys-53 is the most reactive residue and forms a covalent dimer also in SH-SY5Y DJ-1-transfected cells, but modification of Cys-106 induces the most severe structural perturbations; Cys-46 is not reactive. The relevance of these covalent modifications to the several functions ascribed to DJ-1 is discussed in the context of the cell response to a dopamine-derived oxidative insult.
authors.affiliation: Department of Chemical Sciences, University of Padova, Padova, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Girotto
authors.forename: Mattia
authors.initials: M
authors.lastname: Sturlese
authors.forename: Massimo
authors.initials: M
authors.lastname: Bellanda
authors.forename: Isabella
authors.initials: I
authors.lastname: Tessari
authors.forename: Rekha
authors.initials: R
authors.lastname: Cappellini
authors.forename: Marco
authors.initials: M
authors.lastname: Bisaglia
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.forename: Stefano
authors.initials: S
authors.lastname: Mammi
mesh_terms: D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry*; D004298:Dopamine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D015513:Oncogene Proteins / Q000737:chemistry*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D000071617:Protein Deglycase DJ-1; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011809:Quinones; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D003545:Cysteine; D004298:Dopamine