期刊
SCIENCE
卷 340, 期 6139, 页码 1451-1455出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1237908
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资金
- Parkinson Society Canada
- Canadian Institutes of Health Research [MOP-62714, MOP-14219]
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 Cys(431) 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.
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