title: Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations.
abstract: Loss of parkin function is a predominant cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for sporadic Parkinson disease. We have recently demonstrated that a wide variety of Parkinson disease-linked stressors, including dopamine (DA), induce parkin solubility alterations and promote its aggregation within the cell, a phenomenon that may underlie the progressive susceptibility of the brain to degeneration. The vulnerability of parkin to stress-induced modification is likely due to its abundance of cysteine residues. Here, we performed a comprehensive mutational analysis and demonstrate that Cys residues residing both within and outside of the RING-IBR (in between RING fingers)-RING domain of parkin are important in maintaining its solubility. The majority of these Cys residues are highly conserved in parkin across different species and potentially fulfil important structural roles. Further, we found that both parkin and HHARI (human homologue of Drosophila ariadne), another RING-IBR-RING-type ubiquitin ligase, are comparably more susceptible to solubility alterations induced by oxidative and nitrosative stress when compared with other non-RING-IBR-RING Cys-containing enzymes. However, parkin appears to be uniquely sensitive to DA-mediated stress, the specificity of which is likely due to DA modification of 2 Cys residues on parkin (Cys-268 and Cys-323) that are distinct from other RING-IBR-RING members.
authors.affiliation: Neurodegeneration Research Laboratory and Parkinson's Disease and Movement Disorders Center, National Neuroscience Institute, Singapore 308433.
authors.forename: Esther S P
authors.initials: ES
authors.lastname: Wong
authors.forename: Jeanne M M
authors.initials: JM
authors.lastname: Tan
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Zhenshui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shiam-Peng
authors.initials: SP
authors.lastname: Tay
authors.forename: Norazean
authors.initials: N
authors.lastname: Zaiden
authors.forename: Han Seok
authors.initials: HS
authors.lastname: Ko
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry*; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000378:metabolism; D004330:Drosophila; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012995:Solubility; D013045:Species Specificity; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003545:Cysteine; D004298:Dopamine