Structure of parkin reveals mechanisms for ubiquitin ligase activation.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Sequence Data, Mutation, Parkinson Disease, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Rats, Ubiquitin-Protein Ligases, Ubiquitination, Zinc Fingers
Amino Acid Sequence, Animals, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Sequence Data, Mutation, Parkinson Disease, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Rats, Ubiquitin-Protein Ligases, Ubiquitination, Zinc Fingers
Science
Date: Jun. 21, 2013
PubMed ID: 23661642
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