Structure of parkin reveals mechanisms for ubiquitin ligase activation - PubMed (original) (raw)

. 2013 Jun 21;340(6139):1451-5.

doi: 10.1126/science.1237908. Epub 2013 May 9.

Véronique Sauvé, Karl Grenier, Marjan Seirafi, Matthew Y Tang, Marie Ménade, Sameer Al-Abdul-Wahid, Jonathan Krett, Kathy Wong, Guennadi Kozlov, Bhushan Nagar, Edward A Fon, Kalle Gehring

Affiliations

• PMID: 23661642
• DOI: 10.1126/science.1237908

Structure of parkin reveals mechanisms for ubiquitin ligase activation

Jean-François Trempe et al. Science. 2013.

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.

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