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Autoregulation of Parkin activity through its ubiquitin-like domain


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.

Type Journal
ISBN 1460-2075 (Electronic) 0261-4189 (Linking)
Authors Chaugule, V. K.; Burchell, L.; Barber, K. R.; Sidhu, A.; Leslie, S. J.; Shaw, G. S.; Walden, H.;
Publisher Name EMBO J
Published Date 2011-12-01 00:00:00
Published Volume 30
Published Issue 14
Published Pages 2853-67
Status Published In-print
OpenAccess Link Chaugule emboj2011204a.pdf