Autoregulation of Parkin activity through its ubiquitin‐like domain
Identifieur interne : 000389 ( Main/Exploration ); précédent : 000388; suivant : 000390Autoregulation of Parkin activity through its ubiquitin‐like domain
Auteurs : Viduth K. Chaugule [Royaume-Uni] ; Lynn Burchell [Royaume-Uni] ; Kathryn R. Barber [Canada] ; Ateesh Sidhu [Royaume-Uni] ; Simon J. Leslie [Royaume-Uni] ; Gary S. Shaw [Canada] ; Helen Walden [Royaume-Uni]Source :
- The EMBO Journal [ 0261-4189 ] ; 2011-07-20.
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.
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DOI: 10.1038/emboj.2011.204
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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.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Chaugule, Viduth K" sort="Chaugule, Viduth K" uniqKey="Chaugule V" first="Viduth K" last="Chaugule">Viduth K. Chaugule</name></region><name sortKey="Burchell, Lynn" sort="Burchell, Lynn" uniqKey="Burchell L" first="Lynn" last="Burchell">Lynn Burchell</name><name sortKey="Leslie, Simon J" sort="Leslie, Simon J" uniqKey="Leslie S" first="Simon J" last="Leslie">Simon J. Leslie</name><name sortKey="Sidhu, Ateesh" sort="Sidhu, Ateesh" uniqKey="Sidhu A" first="Ateesh" last="Sidhu">Ateesh Sidhu</name><name sortKey="Walden, Helen" sort="Walden, Helen" uniqKey="Walden H" first="Helen" last="Walden">Helen Walden</name></country><country name="Canada"><region name="Angleterre"><name sortKey="Barber, Kathryn R" sort="Barber, Kathryn R" uniqKey="Barber K" first="Kathryn R" last="Barber">Kathryn R. Barber</name></region><name sortKey="Shaw, Gary S" sort="Shaw, Gary S" uniqKey="Shaw G" first="Gary S" last="Shaw">Gary S. Shaw</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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