title: 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 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.
authors: McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors: Jean-François
authors: JF
authors: Trempe
authors: Véronique
authors: V
authors: Sauvé
authors: Karl
authors: K
authors: Grenier
authors: Marjan
authors: M
authors: Seirafi
authors: Matthew Y
authors: MY
authors: Tang
authors: Marie
authors: M
authors: Ménade
authors: Sameer
authors: S
authors: Al-Abdul-Wahid
authors: Jonathan
authors: J
authors: Krett
authors: Kathy
authors: K
authors: Wong
authors: Guennadi
authors: G
authors: Kozlov
authors: Bhushan
authors: B
authors: Nagar
authors: Edward A
authors: EA
authors: Fon
authors: Kalle
authors: K
authors: Gehring
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease; D020734:Parkinsonian Disorders; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D016335:Zinc Fingers
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein