Publication Date:
2013-05-11
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trempe, Jean-Francois -- Sauve, Veronique -- Grenier, Karl -- Seirafi, Marjan -- Tang, Matthew Y -- Menade, Marie -- Al-Abdul-Wahid, Sameer -- Krett, Jonathan -- Wong, Kathy -- Kozlov, Guennadi -- Nagar, Bhushan -- Fon, Edward A -- Gehring, Kalle -- MOP-14219/Canadian Institutes of Health Research/Canada -- MOP-62714/Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 Jun 21;340(6139):1451-5. doi: 10.1126/science.1237908. Epub 2013 May 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23661642" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Catalytic Domain
;
Crystallography, X-Ray
;
Enzyme Activation
;
Hydrophobic and Hydrophilic Interactions
;
Models, Molecular
;
Molecular Sequence Data
;
Mutation
;
Parkinson Disease
;
Parkinsonian Disorders
;
Protein Binding
;
Protein Conformation
;
Protein Folding
;
Protein Structure, Tertiary
;
Rats
;
Ubiquitin-Protein Ligases/*chemistry/genetics/*metabolism
;
Ubiquitination
;
Zinc Fingers
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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