You are currently viewing the abstract.View Full Text
Inactivation of parkin, an E3 ubiquitin ligase, is responsible for a familial form of Parkinson's disease and may be involved in sporadic forms as well. Trempe et al. (p. 1451, published online 9 May) present the crystal structure of full-length parkin in an autoinhibited configuration. Guided by the structure, mutations were designed that activated parkin both in vitro and in cells. Because parkin is neuroprotective, the structure provides a framework for enhancing parkin function as a therapeutic strategy in Parkinson's disease.
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.