Structure of Parkin Reveals Mechanisms for Ubiquitin Ligase Activation

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Science  09 May 2013:

DOI: 10.1126/science.1237908

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Mutations in the Parkin gene are responsible for an autosomal recessive form of Parkinson’s disease. The parkin protein is a RING-In-Between-RING (RBR) E3 ubiquitin ligase, which exhibits low basal activity. Here, we describe the crystal structure of full-length parkin. The structure shows parkin in an auto-inhibited state and provides insight into how it is activated. RING0 occludes the ubiquitin acceptor site Cys431 in RING2, whereas a repressor element of parkin (REP) 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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