Structure of Parkin Reveals Mechanisms for Ubiquitin Ligase Activation
Abstract
Mutations in the PARK2 (parkin) gene are responsible for an autosomal recessive form of Parkinson’s disease. The parkin protein is a RING-in-between-RING E3 ubiquitin ligase that exhibits low basal activity. We describe the crystal structure of full-length rat parkin. The structure shows parkin in an autoinhibited state and provides insight into how it is activated. RING0 occludes the ubiquitin acceptor site Cys431 in RING2, whereas a repressor element of parkin binds RING1 and blocks its E2-binding site. Mutations that disrupted these inhibitory interactions activated parkin both in vitro and in cells. Parkin is neuroprotective, and these findings may provide a structural and mechanistic framework for enhancing parkin activity.
- Publication:
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Science
- Pub Date:
- June 2013
- DOI:
- 10.1126/science.1237908
- Bibcode:
- 2013Sci...340.1451T
- Keywords:
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- BIOCHEM Cell-Biology, Genetics, Biochemistry