Autoregulation of Parkin activity through its ubiquitin-like domain

Chaugule, V. K. , Burchell, L., Barber, K. R., Sidhu, A., Leslie, S. J., Shaw, G. s. and Walden, H. (2011) Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO Journal, 30(14), pp. 2853-2867. (doi: 10.1038/emboj.2011.204) (PMID:21694720) (PMCID:PMC3160258)

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Abstract

Parkin is an E3‐ubiquitin ligase belonging to the RBR (RING–InBetweenRING–RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin‐like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C‐terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3‐ligase activity.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chaugule, Dr Viduth and Walden, Professor Helen
Authors: Chaugule, V. K., Burchell, L., Barber, K. R., Sidhu, A., Leslie, S. J., Shaw, G. s., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075
Published Online:21 June 2011

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