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
November 21, 2000
- Agency: NINDS NIH HHS, Id: NS38377
- Amino Acid Sequence
- Binding Sites
- Cell Cycle Proteins
- Cell Line
- Cloning, Molecular
- Molecular Sequence Data
- Nerve Tissue Proteins
- Parkinson Disease
- Recombinant Proteins
- Sequence Alignment
- Sequence Homology, Amino Acid
- Synaptic Vesicles
- Ubiquitin-Conjugating Enzymes
- Ubiquitin-Protein Ligases
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