Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations

Esther S.P. Wong, Jeanne M.M. Tan, Cheng Wang, Zhenshui Zhang, Shiam Peng Tay, Norazean Zaiden, Seok Ko Han, Valina L. Dawson, Ted M. Dawson, Kah Leong Lim

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)12310-12318
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number16
DOIs
StatePublished - Apr 20 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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