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PMID:11078524

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Citation

Zhang, Y, Gao, J, Chung, KK, Huang, H, Dawson, VL and Dawson, TM (2000) Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl. Acad. Sci. U.S.A. 97:13354-9

Abstract

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.

Links

PubMed PMC27228 Online version:10.1073/pnas.240347797

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PRKN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Z2Q6

F

Seeded From UniProt

complete

MOUSE:SEPT5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O60260

F

Seeded From UniProt

complete

HUMAN:PRKN2

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PRKN2

GO:0004842: ubiquitin-protein ligase activity

ECO:0000314:

F

Figure 4C shows that ubiquitination of CDCrel-1 is significantly increased in the presence of Parkin.

complete
CACAO 3929


See also

References

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