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Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1.

Parkinson's disease is a common neurodegenerative disorder in which familial-linked genes have provided novel insights into the pathogenesis of this disorder. Mutations in Parkin, a ring-finger-containing protein of unknown function, are implicated in the pathogenesis of autosomal recessive familial Parkinson's disease. Here, we show that Parkin binds to the E2 ubiquitin-conjugating human enzyme 8 (UbcH8) through its C-terminal ring-finger. Parkin has ubiquitin-protein ligase activity in the presence of UbcH8. Parkin also ubiquitinates itself and promotes its own degradation. We also identify and show that the synaptic vesicle-associated protein, CDCrel-1, interacts with Parkin through its ring-finger domains. Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1. Familial-linked mutations disrupt the ubiquitin-protein ligase function of Parkin and impair Parkin and CDCrel-1 degradation. These results suggest that Parkin functions as an E3 ubiquitin-protein ligase through its ring domains and that it may control protein levels via ubiquitination. The loss of Parkin's ubiquitin-protein ligase function in familial-linked mutations suggests that this may be the cause of familial autosomal recessive Parkinson's disease.

Pubmed ID: 11078524


  • Zhang Y
  • Gao J
  • Chung KK
  • Huang H
  • Dawson VL
  • Dawson TM


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 21, 2000

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS38377

Mesh Terms

  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle Proteins
  • Cell Line
  • Cloning, Molecular
  • Humans
  • Ligases
  • Methionine
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Parkinson Disease
  • Recombinant Proteins
  • Septins
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Synaptic Vesicles
  • Transfection
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Ubiquitins