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Autoregulation of Parkin activity through its ubiquitin‐like domain
Author(s) -
Chaugule Viduth K,
Burchell Lynn,
Barber Kathryn R,
Sidhu Ateesh,
Leslie Simon J,
Shaw Gary S,
Walden Helen
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.204
Subject(s) - biology , parkin , ubiquitin , autoregulation , ubiquitin protein ligases , deubiquitinating enzyme , ubiquitins , microbiology and biotechnology , domain (mathematical analysis) , ubiquitin ligase , computational biology , genetics , gene , endocrinology , medicine , disease , parkinson's disease , mathematical analysis , mathematics , blood pressure
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.